%PDF-1.3 % 16 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 39 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 26 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 14 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 3 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 10 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 17 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 1 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 35 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 8 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 36 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 4 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 7 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 22 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 13 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 5 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 40 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 25 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 6 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 28 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 33 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 12 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 38 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 29 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 15 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 18 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 32 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 9 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 34 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 20 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 37 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 19 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 24 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 31 0 obj <>>>/BBox[0 0 612 792]/Length 55>>stream xs w3T04PI2P0T5T0P02S04S  @$P5 )1 endstream endobj 11 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 21 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 30 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 23 0 obj <>>>/BBox[0 0 612 792]/Length 53>>stream xs w3T04PI2P0T5T0q-Br44C@B 9 s(P endstream endobj 27 0 obj <>>>/BBox[0 0 612 792]/Length 54>>stream xs w3T04PI2P0T5TR Ɩf !\!Y\ !p)P endstream endobj 42 0 obj <>stream Acrobat Distiller 8.1.0 (Windows); modified using iText 4.2.0 by 1T3XT Arbortext Advanced Print Publisher 9.0.114/W 2016-08-10T22:45:42-07:00 2016-08-05T10:15:20+05:30 application/pdf NAT-2016-0607-ver9-Shemesh_4P 223..235 uuid:d6edfc7b-4a04-47c5-ae3e-ca48ef0b51c9 uuid:e6fc9421-fbcb-41fd-ab24-62f5bb5660da endstream endobj 43 0 obj <>stream x+| endstream endobj 44 0 obj <>stream xS**T0T0Bih]D. r^j endstream endobj 45 0 obj <>stream x+| endstream endobj 46 0 obj <>stream xS**T0T0Bil])D. qgj endstream endobj 47 0 obj <>stream x+| endstream endobj 48 0 obj <>stream xS**T0T0Bid]D. qdj endstream endobj 49 0 obj <>stream x+| endstream endobj 50 0 obj <>stream xS**T0T0Bid]%D. rs endstream endobj 51 0 obj <>stream x+| endstream endobj 52 0 obj <>stream xS**T0T0Bih] D. pa endstream endobj 53 0 obj <>stream x+| endstream endobj 54 0 obj <>stream xS**T0T0BiU)D* 9V endstream endobj 55 0 obj <>stream x+| endstream endobj 56 0 obj <>stream xS**T0T0Bil]D. rs endstream endobj 57 0 obj <>stream x+| endstream endobj 58 0 obj <>stream xS**T0T0Bil]D. pa endstream endobj 59 0 obj <>stream x+| endstream endobj 60 0 obj <>stream xS**T0T0Bih] 9D. qaj endstream endobj 61 0 obj <>stream x+| endstream endobj 62 0 obj <>stream xS**T0T0BiUD* 8 endstream endobj 63 0 obj <>stream x+| endstream endobj 64 0 obj <>stream xS**T0T0Bid]1D. pa endstream endobj 65 0 obj <>stream x+| endstream endobj 66 0 obj <>stream xS**T0T0BiU!D. _e1 endstream endobj 67 0 obj <>stream x+| endstream endobj 68 0 obj <>stream xS**T0T0BiUD* : endstream endobj 70 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 62.022 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(low-density)-417.5(lipoprotein-related)-423.7(receptor,)-419(with)-414.5(eventual)-415.7(en-)]TJ 0 -1.1174 TD [(docytosis)-523.6(and)-522.8(delivery)-524(to)-520.7(endosomes)-519.9(and)-522.8(lysosomes)-524.5(en-)]TJ 0 -1.1116 TD [(hancing)-632.2(elimination)-626.9(and)-626.5(maintaining)-632.5(circulating)-632.4(plasma)]TJ T* [(levels)-423.7(\()]TJ /F9 1 Tf 3.0987 0 TD (*)Tj /F3 1 Tf 1.0022 0 TD [(24)-164.6(mg/mL\))-425.1(in)-422.8(mice)-422.8([6].)-421.4(While)-423.9(A2M)-425.5(makes)-423.6(up)]TJ -4.1009 -1.1116 TD [(only)-344.4(a)-342.1(very)-345.4(small)-347.8(fraction)-345.4(of)-347.7(plasma)-344.2(proteins,)-347.5(upregulation)]TJ 0 -1.1174 TD [(and/or)-330.4(downregulation)-330(of)-330.5(A2M)-327.6(in)-324.9(circulation)-332.9(and)-327(extravas-)]TJ 0 -1.1116 TD [(cular)-203.8(space)-204.6(have)-208.3(been)-202.6(linked)-203.9(to)-203.9(immunological)-203.9(abnormalities)]TJ T* [([79],)-371.7(tissue)-376.3(inammation,)-377.7(Alzheimer)-378.6(disease)-379.6([10,11],)-370.5(and)]TJ 0 -1.1174 TD [(numerous)-638.8(cytokine-related)-645.9(diseases)-639.7([12].)-635.6(In)-641.5(several)-638.9(in-)]TJ 0 -1.1116 TD [(stances,)-509.7(A2M)-506.2(has)-511.1(proven)-508.8(exceedingly)-506.6(useful)-508.8(as)-510(a)-509.1(direct)]TJ T* [(clinical)-283.5(biomarker)-284.2(for)-279.7(numerous)-281.7(disorders)-287.2([1315].)]TJ 1.0137 -1.1174 TD [(Our)-292.1(interest)-293.5(in)-296.1(A2M)-293.1(is)-290.1(in)-296.1(regard)-291.1(to)-296.1(its)-291.3(effect)-298.1(on)-290.2(the)-292.6(phar-)]TJ -1.0137 -1.1116 TD [(macokinetics)-411(\(PKs\))-403.4(and)-401.9(pharmacodynamics)-411.7(\(PDs\))-403.4(of)-399.6(anti-)]TJ T* [(sense)-721.6(oligonucleotides)-718.5(\(ASOs\))-722.1(because)-720.6(it)-716.7(is)-716.3(generally)]TJ T* [(believed)-237.2(that)-242(protein)-233.7(binding)-238.4(and)-234.8(shufing)-238.9(play)-236.1(an)-233.7(important)]TJ 0 -1.1174 TD [(role)-282.1(on)-278.7(tissue)-284.1(distribution,)-282(including)-282.2(the)-275.3(target)-285.6(compartment)]TJ 0 -1.1116 TD [([16,17].)-508.7(RNA)-507.2(targeted)-513.6(drug)-505.5(development)-512.4(using)-506.5(ASOs)-512.6(is)]TJ T* [(recognized)-200.1(as)-193.2(a)-198.1(broad)-190.9(and)-194.5(diverse)-200(platform)-195.7(spanning)-194.2(multiple)]TJ 0 -1.1174 TD [(therapeutic)-310.9(areas)-308.3(for)-308.5(numerous)-304.7(rare)-306.2(disease,)-313.9(cardiovascular,)]TJ 0 -1.1116 TD [(neurological,)-245.1(and)-234.9(metabolic)-245.4(disorders.)-238.8(Over)-242.6(three)-238.3(decades)-242.6(of)]TJ T* [(exhaustive)-175.8(research)-174.5(has)-177.1(established)-176.9(ASOs)-172.8(into)-171.7(a)-175(more)-168(mature,)]TJ 0 -1.1174 TD [(efcient,)-499.6(and)-494(well-accepted)-500.6(techn)-8(ology)-489.5(with)-500.9(several)-494.9(suc-)]TJ 0 -1.1116 TD [(cessful)-251.7(commercialized)-261.4(products)-251.8(to)-250(date)-254.5([18].)]TJ 1.0137 -1.1116 TD [(Currently,)-263.4(the)-263.8(RNase)-263(H1)-262.3(degradation)-263.5(pathway)-270.2(is)-261.3(the)-258(most)]TJ -1.0137 -1.1174 TD [(advanced)-670.1(and)-672.6(well)-669.1(understood)]TJ /F7 1 Tf 14.0882 0 TD [(in)-670.5(vivo)]TJ /F3 1 Tf 3.7956 0 TD [(mechanism)-672.4(for)]TJ -17.8839 -1.1116 TD [(cleavage)-302.7(of)-295.9(targeted)-300.5(RNA,)-297.5(yet)-298.3(signicant)-301.4(other)-300.5(ASO)-298.6(mech-)]TJ T* [(anisms)-348.6(have)-352.3(been)-352.3(described)-347.4(and)-350(utilized)-351.5(spanning)-349.7(multiple)]TJ T* [(targets)-349.9(and)-350(organs)-353.1([1921].)-350.9(O)-7.7(p)-12.6(t)-7(i)-12.7(m)-8.1(i)-12.7(z)-8(a)-13.8(t)-12.7(i)-7(o)-12.6(n)-6.9(s)-358(t)-12.7(o)-358.2(t)-12.7(h)-6.9(e)-359.4(b)-12.6(a)-8(s)-12.4(e)-359.4(p)-12.6(a)-8(i)-12.7(r)]TJ 0 -1.1174 TD .0133 Tc [(ch)6.4(em)5.2(is)6.6(tri)6.3(e)-.5(s)-269.8(o)6.4(f)-270(A)-.2(S)6.6(O)-.2(s)-269.8(h).7(a)5.3(v).7(e)-265.4(g).7(iv)6.4(en)-270(r)6.5(i).6(s)6.6(e)-271.2(to)-270(i)6.3(n).7(c)5.3(r).7(ea)5.3(se)5.3(d)-270(t).6(o)6.4(l).6(er)6.5(an)6.4(ce)]TJ 0 -1.1116 TD .0118 Tc [(an)4.9(d)-346.4(s)-.6(i)4.8(gni)4.8(can)4.9(tly)-346.4(enh)4.9(a)-2(n)4.9(c)-2(ed)-346.4(po)4.9(ten)4.9(c)-2(y)4.9(,)-348.7(o)4.9(fferi)4.8(ng)-346.4(l)4.8(e)-2(ss)-346.2(f)5(r)-.8(equent)]TJ T* .0127 Tc [(do)5.8(sin)5.8(g)-374.3(reg)5.8(i)0(men)5.8(s).3(,)-376.6(a)4.7(ccess)-374.1(t)5.7(o)-380.1(m)4.6(ul)5.7(ti)5.7(ple)-375.5(r)5.9(out)5.7(es)-374.1(of)-374.3(ad)5.8(mi)5.7(ni)5.7(str)5.9(a)-1.1(-)]TJ 0 -1.1174 TD .0122 Tc [(ti)5.2(on)5.3(,)-342.6(a)-1.6(n)5.3(d)-346(r)5.4(e)-1.6(du)5.3(ced)-340.2(und)5.3(es)5.5(irabl)5.2(e)-347.2(s)5.5(i)-.5(d)5.3(e)-347.2(effect)5.2(s)-345.8([)5.4(22)5.3(].)-342.6(Curr)5.4(en)5.3(tly)5.3(,)]TJ 0 -1.1116 TD [(AS)5.6(O)-415.9(d)5.4(evelo)5.4(p)-.3(men)5.4(t)-415.1(is)-409.1(ev)5.4(olv)5.4(i)-.4(n)5.4(g)-415(wi)5.3(th)-409.3(numer)5.5(ou)5.4(s)-414.8(p)-.3(r)5.5(e)-1.5(clin)5.4(ical)]TJ T* .013 Tc [(an)6.1(d)-293.4(a)5(dv)6.1(anc)5(e)-.8(d)-287.6(s).6(t)6(a)-.8(g)6.1(e)-294.5(c)5(lin)6.1(ic)5(al)-287.7(pro)6.1(gr)6.2(am)4.9(s)-293.2(o).4(f)6.2(f).4(e)5(r).4(in)6.1(g)-293.4(g)6.1(re)5(at)-293.5(p)6.1(r).4(o)6.1(m)-.8(-)]TJ 0 -1.1174 TD .012 Tc [(is)5.3(e)-284(f)5.2(or)-277(un)5.1(met)-277.2(c)-1.8(l)5(i)-.7(ni)5(cal)-277.2(n)-.6(eeds)5.3(.)]TJ 1.0137 -1.1116 TD 0 Tc [(From)-425.9(a)-422.7(development)-426(perspective)-11(,)-423.9(oligonucleotides)-424.8(have)]TJ -1.0137 -1.1116 TD [(been)-283.2(shown)-276.9(to)-278.8(have)-283.2(pervasive)-278.3(and)-280.9(tight)-282.4(binding)-278.7(interactions)]TJ T* [(with)-374.2(proteins)-372.9([23],)-370.6(and)-373.1(plasma)-373(proteins)-378.6(such)-368.2(as)-377.5(A2M)-367.9(may)]TJ 0 -1.1174 TD [(bind)-367.4(to)-365.2(ASOs)-362.9(with)-368.4(high)-361.6(afnity.)-369.5(Thus,)-365.9(knocking)-361.5(out)-366.3(A2M)]TJ 0 -1.1116 TD [(could)-335.1(potentially)-337.6(alter)-336.4(organ,)-332.6(suborgan,)-335.7(and)-332.8(subcellular)-338.3(up-)]TJ T* [(take,)-194.6(directly)-195.8(affecting)-197.9(the)-194.7(PK)-193(and)-194.5(PD)-193(properties)-197.7(of)-192.2(ASOs.)-193.5(As)]TJ 0 -1.1174 TD [(such,)-285.3(the)-281.1(biodistribution,)-279.7(uptake,)-283.2(and)-286.7(clearance)-287.7(mechanisms)]TJ 0 -1.1116 TD [(using)-293.4(an)-297.1(A2M)-298.8(and)-292.4(murinoglobulin)-299.4(double-knockout)-295.6(\(DKO\))]TJ T* [(model)-209.6(could)-214.1(alter)-209.6(the)-211.9(pharmacological)-214(response)-212.3(of)-209.5(ASOs)-213.1(and)]TJ 0 -1.1174 TD [(are)-282.1(worthy)-284(of)-278.6(investigation.)]TJ 1.0137 -1.1116 TD [(As)-296.6(an)-297.1(internal)-305.2(tool)-298.4(research)-301.2(compound,)-296.9(ION-353382)-300.7(a)-301.8(5)0(-)]TJ -1.0137 -1.1116 TD [(10-5,)-353.4(20-mer)-354.5(methoxyethyl)-357(\()-81.7(MOE\))-352.9(gapmer)-355.7(composed)-357.8(of)-353.5(a)]TJ 0 -1.1174 TD [(phosphorothioate)-659.5(backbone)-657.4(targeting)-651.9(scavenger)-659.4(receptor)]TJ 0 -1.1116 TD [(class)-197.6(B)-192.2(type)-195.8(I)-191.1(\(SRB1\))-198.5(mRNA)-192.7(is)-192.2(evaluated)-199.1(in)-192.4(this)-194.5(study.)-193.2(SRB1)]TJ T* [(protein)-441.1(is)-439.9(widely)-440.9(expressed)-445(in)-440.1(the)-442.3(liver)-438.9(as)-440.9(a)-445.8(high-density)]TJ T* [(lipoprotein)-399.7(\(HDL\))-405.8(receptor)-398.3(and)-401.9(has)-395.9(high)-402(afnity)-400.6(toward)-400.4(a)]TJ 0 -1.1174 TD [(wide)-329.1(variety)-327(of)-318.9(lipid-like)-329.6(ligands)-325.7(and)-327(mediates)-324.6(lipid)-328.4(uptake)]TJ 0 -1.1116 TD [(playing)-383.5(a)-382.4(crucial)-391.6(role)-380(in)-382.5(metabolism)-390.4(processes)-387.2([24].)-382.1(Thus,)]TJ T* [(functional)-353.5(changes)-356.6(of)-347.7(SRB1)-351.9(activity)-351.5(using)-351(ASOs)-351.4(to)-353.7(inhibit)]TJ 0 -1.1174 TD [(mRNA)-187(expression)-185.8(may)-184.2(affect)-188.7(HDL,)-188.2(cholesterol,)-186.2(lipoproteins,)]TJ 0 -1.1116 TD [(and)-280.9(numerous)-281.7(other)-283.2(ligands.)]TJ 1.0137 -1.1116 TD [(Herein,)-416.5(in)-411.3(the)-413.5(current)-419(work,)-411.9(we)-418.9(explore)-413.3(comprehensive)]TJ -1.0137 -1.1174 TD [(PK/PD-related)-382.4(investigations)-375.1(for)-371.9(ASOs)-380.2(using)-374.1(an)-372(A2M)-373.7(and)]TJ 0 -1.1116 TD [(murinoglobulin)-391.5(DKO)-391.8(murine)-389.2(model.)-391.6(Our)-384.3(research)-393.3(aims)-392.6(to)]TJ T* [(provide)-256.6(a)-249.9(detailed)-254.6(account)-259(into)-252.3(describing)-255.3(the)-252.3(effect)-257.8(of)-249.8(A2M)]TJ 0 -1.1174 TD [(knockout)-292.3(on)-290.2(the)-292.6(PK/PD)-295(of)-290.2(ION-353382)-294.9(targeting)-294.8(SRB1)-294.3(ad-)]TJ 0 -1.1116 TD [(ministrated)-350(as)-343(a)-347.8(single)-347.7(dose.)-348.6(Our)-344(investigations)-346.3(include)-350.1(\(1\))]TJ 25.504 67.9184 TD [(evalu)-8(ating)-358.3(plasma)-367.2(C)]TJ 7.3823 0 0 6.5614 395.9999 723.5148 Tm (trough)Tj 9.843 0 0 9.843 418.9038 725.1588 Tm [(and)-361.6(liver)-364(and)-361.6(kidney)-365(distribution)]TJ -10.7534 -1.1174 TD [(kinetics,)-222.1(\(2\))-216.4(describing)-220.7(pharmacological)-225.5(differences)-224(using)-212.8(an)]TJ 0 -1.1116 TD [(inhibitory)-328.3(effect)-321.2(liver)-323.7(exposure)-321.9(respon)-7.5(se)-320(model,)-322.5(\(3\))-320(hepatic)]TJ T* [(uptake)-308.6(differences)-310.4(by)-301.7(immunohistochemistry)-310.5(\(IHC\),)-304.5(\(4\))-308.5(de-)]TJ T* [(scribing)-545.7(the)-546(degree)-540(of)-543.6(total)-542.7(plasma)-545.8(protein)-544.7(binding)-543.6(and)]TJ 0 -1.1174 TD [(protein)-360.4(binding)-359.3(proling,)-357.9(\(5\))-354.6(conrming)-363.6(no)-353.5(signicant)-364.7(dif-)]TJ 0 -1.1116 TD [(ferences)-226.3(in)-221.2(total)-220.2(protein,)-219.9(albumin,)-215.4(histidine-rich)-225.5(glycoprotein)]TJ T* [(\(HRG\),)-368.8(and)-367.3(immunoglo)-6.9(bulins,)-361.4(and)-367.3(nally,)-368.4(\(6\))-366.1(plasma)-373(pro-)]TJ 0 -1.1174 TD [(teome)-285.7(ngerprinting.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 313.0582 612.5668 Tm [(Materials)-339(and)-331.9(Methods)]TJ /F10 1 Tf 0 -1.8336 TD (Materials)Tj /F3 1 Tf 9.843 0 0 9.843 323.0361 579.6849 Tm [(Sod)14.1(ium)-194.7(pho)14(sph)14.2(ate)-195.8(dib)13.8(asi)12.9(c,)-201.5(tri)13.8(eth)12.7(yla)12.7(mm)12.6(oni)13.8(um)-199.3(bic)12.7(arb)12.9(ona)12.8(te,)]TJ -1.0137 -1.1116 TD [(phe)12.8(nol)13.8(:ch)12.7(lor)13.9(ofo)14(rm:)12.6(iso)14(am)12.7(yl)-555.3(alc)11.5(oh)15.1(ol)-555.3(25:)13.8(24:)13.8(1,)-545.9(Tri)12.7(s\(h)14.2(ydr)14(oxy)14(-)]TJ 0 -1.1174 TD [(met)11.4(hyl)13.8(\)am)11.6(ino)13.8(me)12.7(tha)12.7(ne,)-554(eth)12.7(yle)12.7(ned)12.8(iam)17.2(ine)12.7(tet)12.6(raa)11.7(cet)11.5(ic)-556.4(aci)11.5(d,)-557.5(2-)]TJ 0 -1.1116 TD [(mer)11.6(cap)11.7(toe)12.7(tha)12.7(nol)13.8(,)-475.7(H)]TJ 7.3823 0 0 6.5614 392.4849 545.1589 Tm (2)Tj 9.843 0 0 9.843 396.17 546.803 Tm [(O,)-471.9(ace)10.5(ton)13.8(itr)13.8(ile)12.6(,)-481.5(eth)12.7(ano)18.6(l,)-477(tri)13.8(eth)12.7(yla)12.7(min)12.6(e,)]TJ -8.4437 -1.1116 TD [(hex)12.8(au)13(oro)14(iso)14(pro)14(pan)12.8(ol,)-155.5(and)-160(he)13.9(mat)11.5(oxy)14(lin)-159.1(we)13(re)-164.6(pur)14(cha)11.6(sed)-154(fro)14(m)]TJ T* [(Sig)14(ma-)11.6(Ald)13(ric)12.7(h)-450.4(\(St)14(.)-452.7(Lou)12.8(is,)-443.3(MO\))12.2(.)-452.7(Twe)10.7(en-)12.8(20)-445.7(was)-442.9(pur)14(cha)11.6(sed)]TJ 0 -1.1174 TD [(fro)14(m)-284.5(Pro)14.2(me)12.7(ga)-279.8(Cor)13(por)14(ati)12.6(on)-272.9(\()-75.9(Mad)11.9(iso)14(n,)-275.2(WI\))11.8(.)-279.9(MSD)-269.9(blo)13.9(cke)11.7(r)-283.3(A)0(,)]TJ 0 -1.1116 TD [(MSD)-483(rea)11.7(d)-490.7(buf)14(fer)-482.5(T)-491.9(\()0(4)]TJ /F8 1 Tf 9.6878 0 TD ()Tj /F3 1 Tf .5472 0 TD [(\))-490.6(wit)12.8(h)-484.9(sur)14.2(fac)11.7(tan)12.7(t,)-488.5(and)-476.8(MSD)-483(gol)13.8(d)]TJ -10.235 -1.1116 TD [(stre)17.6(pta)12.7(vid)13.8(in)-250(pla)12.7(te)-251.2(wer)12(e)-255.7(pur)14(cha)11.7(sed)-246.2(fro)14(m)-255.7(M)0(e)13(s)0(o)-255.4(S)0(a)14.1(l)0(e)-251.2(Dis)13.2(cov)12.8(ery)]TJ 0 -1.1174 TD [(\(Ro)13(ckv)12.8(ill)13.6(e,)-276.4(MD\))12.2(.)-274.1(Str)14(ata)11.5(-X)-273.7(33)]TJ /F9 1 Tf 11.9687 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(m)-278.8(pol)13.8(ym)13.9(eri)12.7(c)-278.7(and)-269.4(pro)14(tei)12.6(n)-277.6(pre)12.8(-)]TJ -12.5158 -1.1116 TD [(cip)12.7(ita)12.6(tio)13.7(n)-173.9(pla)12.7(te)13.8(s)-173.7(wer)12(e)-169.3(pur)14(cha)11.7(sed)-165.5(fro)14(m)-169.4(Phe)13(nom)12.8(ene)17.4(x)-173.9(\(To)12.8(rra)12.9(nce)11.7(,)]TJ T* [(CA\))12.1(.)-458.4(Pho)14.1(sph)14.2(ate)11.5(-bu)19.8(ffe)12.9(red)-447.9(sal)12.9(ine)-448.1(\(PB)13.1(S\),)-443.2(exp)12.8(res)13(s)-455.9(sup)14.2(ers)13(cri)12.7(pt)]TJ 0 -1.1174 TD [(qPC)13.1(R)-313.1(sup)14.2(erm)11.6(ix)-307.6(uni)13.8(ver)12.8(sal)12.9(,)-314.4(rox)-302.8(ref)12.9(ere)11.7(nc)13.9(e)-319(d)0(y)15.1(e)0(,)-311(exp)12.8(res)13(s)-311.9(sup)14.2(er-)]TJ 0 -1.1116 TD [(scr)13(ipt)-141.8(mix)12.6(,)-153.2(Rib)12.8(oG)14.2(ree)11.7(n,)-148.5(pur)14(eli)12.6(nk)-146.2(pro)-135.7(RNA)-144.3(pur)14(ic)12.8(ati)12.6(on)-146.2(kit)13.7(,)-147.4(gen)12.8(e)]TJ T* [(exp)12.8(res)13(sio)14(n)-507.9(qPC)13.1(R)-503.2(kit)13.7(,)-504.5(sim)12.8(ply)13.8(blu)13.9(e)-509.1(saf)13(est)12.9(ai)13.8(n,)-505.6(DNa)16.8(se)-504.3(I,)-499.8(and)]TJ T* [(ale)11.5(xa-)12.8(488)-233.7(wer)12(e)-249.9(pur)14(ch)13.9(ase)11.8(d)-248.8(fro)14(m)-244.2(Inv)14(itr)13.8(oge)12.8(n)-243(\(Ca)11.8(rls)14.1(bad)12.8(,)-245.3(CA\))12.1(.)]TJ 1.0137 -1.1174 TD [(MSD)-321.7(probes)-318.6(and)-315.5(qPCR)-323.1(primer)-314.3(probe)-323.4(set)-315.4(were)-324.4(purchased)]TJ -1.0137 -1.1116 TD [(from)-201.4(Integrated)-204.8(DNA)-196(Technologies)-202.3(\(Coralville,)-203.7(IA\).)-197.6(Xbridge)]TJ T* [(column)-395(\(50)]TJ /F8 1 Tf 4.9015 0 TD ()Tj /F3 1 Tf .72 0 TD [(2.1)-166.9(mm,)-394(2.5)]TJ /F9 1 Tf 5.0397 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(m\))-389.3(was)-391(purchased)-393.3(from)-391.5(Waters)]TJ -11.2141 -1.1174 TD [(\()-75.9(M)0(i)19.8(l)0(f)20.7(o)0(r)15.1(d)0(,)-298.3(M)0(A)19.1(\))0(.)-298.2(S)0(i)20.9(z)0(e)-304(e)0(x)19.7(c)0(l)19.5(u)0(s)21(i)0(o)15(n)-306.4(co)19.7(lu)20.7(mn)-302.9(\(3)20.9(00)]TJ /F8 1 Tf 17.7917 0 TD ()Tj /F3 1 Tf .7084 0 TD [(4.)18.5(6)-156.6(m)0(m)18.4(,)-308.7(3)]TJ /F9 1 Tf 4.147 0 TD (m)Tj /F3 1 Tf .5414 0 TD (m\))Tj -23.1886 -1.1116 TD [(wa)13(s)-260.1(p)0(u)20.8(r)0(c)14(h)0(a)19.7(s)0(e)19.9(d)-266(fr)20.9(om)-251.1(Se)14.1(pa)19.7(x)-260.3(T)0(e)18.5(c)0(h)19.7(n)0(o)15.1(l)0(o)20.7(g)0(i)20.7(e)0(s)19.9(,)-262.6(In)20.9(c.)-259.1(\(N)20(ew)18.8(ar)19.7(k,)-252.2(DE)18.8(\).)]TJ T* [(Na)13(no)20.8(se)19.9(p)-317.9(3)0(0)20.8(K)-313(om)19.6(eg)13.9(a)-313.3(c)0(e)18.5(n)0(t)20.7(r)0(i)15(f)0(u)20.9(g)0(a)19.7(l)-318(l)20.9(te)19.6(rs)-307.2(we)18.8(re)-308.6(pu)20.8(rc)19.7(ha)19.7(se)19.9(d)-317.9(f)0(r)20.9(o)0(m)]TJ 0 -1.1174 TD [(Pa)14.1(ll)-227.1(Co)14(rp)20.9(or)20.9(at)19.5(io)20.7(n)-243(\()0(A)20(n)0(n)-232.6(A)0(r)20(b)0(o)20.8(r)0(,)-234.9(M)0(I)20(\))0(.)-229.1(S)0(u)21(r)0(f)15.1(a)0(c)18.5(t)0(-)20.7(a)0(m)18.4(p)0(s)-232.4(8)0(0)20.8(,)-239.6(10)20.8(%)-244.1(a)0(n)19.7(d)]TJ 0 -1.1116 TD .0121 Tc [(Tri)5.1(s)-.3(-b)5.2(uf)5.3(fered)-415.2(s)5.4(al)5.1(ine)-410.6(\()-.5(TBS\))-415.2(wer)5.3(e)-416.4(pu)5.2(rch)5.2(a)-1.7(s)5.4(e)-1.7(d)-415.2(f)-.5(r)5.3(o)-.5(m)-416.4(T)4(hermo)]TJ T* 0 Tc [(Sc)14.1(ie)19.6(nt)20.7(i)20.9(c)-238.4(\()0(R)19.8(o)0(c)19.7(k)0(f)15.1(o)0(r)20.9(d)0(,)-229.2(I)0(L)19.7(\))0(.)-229.1(R)0(e)18.6(a)0(d)19.7(y)0(S)21(t)0(r)20.7(i)0(p)-227(I)0(P)15.3(G)-238.1(st)20.9(ri)20.7(ps)15.3(,)-233.8(e)0(q)19.7(u)0(i)14.9(l)0(i)20.6(b)0(r)20.9(a)0(t)19.5(i)0(o)20.7(n)]TJ 0 -1.1174 TD [(bu)15.1(ff)20.9(er)19.7(s)-208.3(I)-208.4(an)19.7(d)-208.4(I)0(I)20.9(,)-205(io)15(do)20.8(ac)18.5(et)19.5(am)18.5(id)20.7(e,)-195.8(30)15.1(%)-203.8(g)0(l)20.7(y)0(c)13.9(e)0(r)19.7(o)0(l)-198.2(s)0(o)21(l)0(u)20.7(t)0(i)20.6(o)0(n)20.8(,)-210.8(pr)20.9(ot)20.7(ei)19.5(n)]TJ 0 -1.1116 TD [(st)15.1(an)19.7(da)19.7(rd)-198(pl)14.9(ug)20.8(s,)-200.2(ov)20.8(er)19.7(la)19.5(y)-208.4(a)0(g)13.9(a)0(r)19.7(o)0(s)21(e)0(,)-201.5(p)0(r)20.9(e)0(c)18.5(a)0(s)19.9(t)-214.3(ge)19.7(l)-208.6(c)0(r)19.7(i)0(t)20.6(e)0(r)14(i)0(o)20.7(n)-208.4(8%)19.8(1)20.8(6%)]TJ T* [(Tr)13.9(is)20.9(H)20(Cl)19.7(,)-205(T)0(r)19.7(i)0(s)15.1()0(g)20.8(l)0(y)20.7(c)0(i)19.5(n)0(e)-199.2(s)0(o)21(d)0(i)20.7(u)0(m)-199.2(d)0(o)20.8(d)0(e)19.7(c)0(y)19.7(l)-208.6(su)21(lf)15(at)19.6(e)-203.8(\()0(S)15.3(D)0(S)20.1(\))-208.4(ru)20.9(nn)20.8(in)20.7(g)]TJ T* [(bu)15.1(ff)20.9(er)-314.4(10)]TJ /F8 1 Tf 3.7035 0 TD ()Tj /F3 1 Tf .5414 0 TD [(,)-326(a)0(n)19.7(d)-323.6(Br)19.8(ad)19.7(fo)20.9(rd)-313.2(to)15(ta)19.6(l)-323.8(p)0(r)20.9(o)0(t)20.7(e)0(i)19.5(n)-323.6(as)19.9(sa)19.9(y)-323.6(w)0(e)18.8(r)0(e)-320.1(p)0(u)20.8(r)0(c)19.7(h)0(a)19.7(s)0(e)19.9(d)]TJ -4.2449 -1.1174 TD [(fr)15.1(om)-291.4(Bi)19.7(o-)15.1(Ra)18.6(d)-300.6(\()0(H)20(e)0(r)14(c)0(u)19.7(l)0(e)19.6(s)0(,)-292.3(C)0(A)18.9(\))0(.)-292.5(P)0(r)15.3(o)0(t)20.7(e)0(i)19.5(n)0(a)19.7(s)0(e)-296.9(K)-301.5(an)13.9(d)-300.6(D)0(A)19.1(B)-307.4(Ch)19.8(ro)20.9(-)]TJ 0 -1.1116 TD [(ma)18.4(ge)13.9(n)-271.8(w)0(e)13(r)0(e)-268.3(p)0(u)20.8(r)0(c)19.7(h)0(a)19.7(s)0(e)19.9(d)-277.6(fr)20.9(om)-268.4(Da)18.8(ko)-267.1(\(C)14.1(ar)19.7(pi)20.7(nt)20.7(er)19.7(ia)19.6(,)-279.9(C)0(A)18.9(\))0(.)-269.4(P)0(r)21(o)0(t)20.7(e)0(i)19.5(n)]TJ T* [(Bl)13.9(oc)19.7(ki)20.7(ng)-422.7(So)21(lu)15(ti)20.6(on)-422.7(wa)18.8(s)-438.6(o)0(b)20.8(t)0(a)19.6(i)0(n)20.7(e)0(d)-423.8(f)0(r)15.2(o)0(m)-423.9(I)0(n)20.9(n)0(o)20.8(v)0(e)19.7(x)-433.1(Bi)13.9(os)21(ci)19.5(en)19.7(ce)18.5(s)]TJ 0 -1.1174 TD [(\(R)14.1(ic)19.6(hm)19.6(on)20.8(d,)-407.7(CA)18.9(\).)-407.7(Se)19.8(co)19.7(nd)20.8(ar)19.7(y)-421.6(a)0(n)19.7(t)0(i)20.6(b)0(o)20.8(d)0(y)20.8(:)-415.9(go)15.1(at)-406.7(an)19.7(ti)20.6(-r)20.9(ab)13.9(bi)20.7(t)-415.9(I)0(g)20.9(G)]TJ 0 -1.1116 TD [(\(H)14.2(RP)20(\))-479.1(w)0(a)18.8(s)-479(pu)20.8(rc)19.7(ha)19.7(se)19.9(d)-479.2(f)0(r)20.9(o)0(m)-470(J)0(a)19.9(c)0(k)13.9(s)0(o)21(n)-479.2(Im)19.6(mu)19.6(no)20.8(Re)18.6(se)19.9(ar)19.7(ch)-469.9(La)18.5(-)]TJ T* [(bo)15.1(ra)19.7(to)20.7(ry)-370.8(\(W)18.6(es)19.9(t)-375.6(G)0(r)20(o)0(v)15.1(e)0(,)-368.6(P)0(A)20.1(\))0(.)-367.4(X)0(y)20(l)0(e)19.6(n)0(e)-372(a)0(n)19.7(d)-375.5(et)19.5(hy)15.1(l)-375.6(a)0(l)19.5(c)0(o)19.7(h)0(o)20.8(l)-381.4(we)18.8(re)]TJ 0 -1.1174 TD .0175 Tc [(pu)4.9(rchased)-323.4(f)-.8(r)4.9(o)-.9(m)-324.6(B)3.9(BC)-324.4(Bio)4.9(c)3.7(hemi)4.8(cal)-323.5(\()-81.5(Mou)4.9(n)-.9(t)-323.5(V)4(er)4.9(no)4.9(n,)-320(WA\).)]TJ 0 -1.1116 TD [(Mu)4.8(ri)4.7(ne-s)5(peci)4.7(c)-560.8(alb)4.8(u)-1(min)-559.7(e)3.6(nzyme-)4.8(li)4.7(n)4.8(k)-1(ed)-565.4(i)4.7(m)-2.2(mu)4.8(no)4.8(so)4.8(rb)4.8(en)4.8(t)]TJ T* .0147 Tc [(a)-4.8(s)2.3(say)-222.5(\()2.1(EL)-4.9(ISA\))-216.7(kit)-216.9(w)-4.5(as)-222.3(purchas)]TJ 12.6483 0 TD .0131 Tc [(ed)-218.4(f)-5.2(r).5(o)-5.3(m)-219.6(Be)-6.4(th)-5.3(yl)-218.5(La)-6.4(bo)-5.3(ra)-6.4(to)-5.3(ri)-5.4(es)]TJ -12.6483 -1.1116 TD [(\()-86(M)-6.3(on)-5.4(tg)-5.4(ome)-6.5(r).4(y)-5.4(,)-433.9(T)-6.6(X)-.5(\))-5.3(.)-433.9(M)-6.3(u).4(r)-5.3(i).3(n)-5.4(e)-.8(-)-5.3(s).6(p)-5.4(eci)-5.5(c)-438.5(I)-5.3(mmu)-5.4(no)-5.4(gl)-5.5(ob)-5.4(ul)-5.5(in)-437.3(G)-6.2(,)]TJ 0 -1.1174 TD .0128 Tc [(M)-6.5(,)-537.8(and)-541.2(A)-536.3(ki)-5.7(ts)-535.3(w)-6.4(e)-1(r)-5.5(e)-536.6(pu)-5.6(rc)-6.7(ha)-6.7(se)-6.7(d)-535.5(f).2(r)-5.5(o).2(m)-536.7(e)-6.7(Bio)-5.6(s).4(c)-6.7(i).1(e)-6.7(n).2(c)-6.8(e)-536.6(\(S)-5.4(an)]TJ 0 -1.1116 TD .0173 Tc [(Di)4.6(eg)4.7(o,)-326(CA\))4.7(.)-331.7(HRG)-324.5(E)-2.3(LIS)4.8(A)-330.2(k)4.7(i)-1.2(t)-329.5(w)3.8(as)-329.2(pu)4.7(rchased)-329.4(f)4.7(ro)4.7(m)-330.6(C)3.7(lo)4.7(ud)4.7(-)]TJ T* .0127 Tc [(C)-6.7(l)0(o)-5.7(n).1(e)-283.3(C)-6.7(or)-5.6(po)-5.7(ra)-6.8(tio)-5.7(n)-282.1(\()-5.6(Hou)-5.7(s).3(t)-5.8(o).1(n)-5.7(,)-278.7(T)-6.9(X)-.8(\))-5.6(.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 313.0582 105.959 Tm 0 Tc (MAM)Tj /F8 1 Tf 6.7246 0 0 5.9768 333.9779 109.9275 Tm (-)Tj /F10 1 Tf .5564 0 TD (/)Tj /F8 1 Tf .2782 0 TD (-)Tj /F10 1 Tf 8.9663 0 0 8.9663 343.3322 105.959 Tm (MUG1)Tj /F8 1 Tf 6.7246 0 0 5.9768 369.1842 109.9275 Tm (-)Tj /F10 1 Tf .5564 0 TD (/)Tj /F8 1 Tf .2782 0 TD (-)Tj /F10 1 Tf 8.9663 0 0 8.9663 381.5432 105.959 Tm [(DKO)-332.6(breeding)]TJ -7.6381 -1.2203 TD [(and)-335.7(routine)-336.5(colony)-331.7(testing)]TJ /F3 1 Tf 9.843 0 0 9.843 323.0361 78.5763 Tm [(C57BL/6-DKO)-208.2(murine-alpha-2-macroglobulin)-212.4(\()-81.7(MAM\))]TJ /F8 1 Tf 7.3823 0 0 6.5614 541.9274 82.9417 Tm (-)Tj /F3 1 Tf .5529 0 TD (/)Tj /F8 1 Tf .2841 0 TD (-)Tj /F3 1 Tf 9.843 0 0 9.843 313.0582 67.5779 Tm [(and)-211.8(murinoglobulin)-207.2(\()-81.7(MUG1\))]TJ /F8 1 Tf 7.3823 0 0 6.5614 428.0314 72 Tm (-)Tj /F3 1 Tf .5529 0 TD (/)Tj /F8 1 Tf .2765 0 TD (-)Tj /F3 1 Tf 9.843 0 0 9.843 440.277 67.5779 Tm [(mice)-209.7(were)-209.2(obtained)-207.2(from)-212.9(the)]TJ -12.9248 -1.1116 TD [(University)-462.5(of)-457.2(California,)-461.6(San)-459.3(Francisco.)-460.1(DKO)-455.2(mice)-463.1(were)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (224)Tj 46.1699 0 TD [(SHEMESH)-334(ET)-338.7(AL.)]TJ ET endstream endobj 82 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 59.7543 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(generated)-348.7(by)-342(recombinan)-10.1(t)-341(DNA)-345.7(construct)-346.3(vectors)-344(targeting)]TJ 0 -1.1174 TD [(the)-396.3(MUG)-397.6(and)-401.9(MAM/MUG)-399.1(genes)-393.5(and)-401.9(were)-393.5(electroporated)]TJ 0 -1.1116 TD [(into)-407.8(embryonal)-405.2(stem)-404.1(cell)-404.4(lines,)-407.6(pups)-401.6(were)-410.7(genotyped,)-401.7(and)]TJ T* [(HE/HE)-355.4(pairs)-352.2(were)-353.2(mated)-354.8(followed)-350.9(by)-347.8(screening)-358.9(for)-348.8(homo-)]TJ T* [(zygous)-284(strains)-279.4([25,26].)-284.1(Both)-282(male)-278.8(and)-280.9(female)-282.1(breeders)-288.5(were)]TJ 0 -1.1174 TD [(setup)-438.6(as)-440.9(exclusive)-439.7(\(HO/HO)]TJ /F8 1 Tf 11.5424 0 TD ()Tj /F3 1 Tf .5529 0 TD [(HO/HO\),)-439.9(and)-442.2(\(WT/WT)]TJ /F8 1 Tf 9.803 0 TD ()Tj /F3 1 Tf .5529 0 TD (WT/)Tj -22.4513 -1.1116 TD [(WT\))-444.5(matings.)-439.8(Breeders)-445.1(and)-436.4(pups)-441.9(were)-439.5(screened)-445.2(by)-434.2(A2M)]TJ T* [(plasma)-373(concentrations.)-375(Whole)-371.9(blood)-368.5(and)-373.1(plasma)-367.2(were)-376.2(col-)]TJ 0 -1.1174 TD [(lected)-315.6(from)-305.1(mice)-313.4(at)-308.8(5)-306.4(weeks)-308(of)-307.4(age)-310.9(and)-309.7(centrifuged)-309.5(using)-310.7(a)]TJ 0 -1.1116 TD [(5415C)-283(Microcentrifuge)-293.1(to)-284.6(collect)-282.3(plasma)-286.6(\(Eppendorf,)-287.4(Ham-)]TJ T* [(burg,)-284.3(Germany\).)]TJ 1.0137 -1.1174 TD [(An)-193.1(ELISA)-187.1(specic)-195.3(for)-193.3(murine)-187.7(A2M)-189.4(was)-195.2(performed)-191.9(using)-189.8(a)]TJ -1.0137 -1.1116 TD [(singleplex)-278.5(assay)-272.4(on)-267.1(the)-275.3(luminex)-269.6(platform)-276.3(using)-270.4(a)-273(polyclonal)]TJ T* [(sheep)-278.3(anti-A2M)-276.9(captu)-8(re)-274(antibody.)-278.6(The)-276.4(standard)-276(curve)-278.5(range)]TJ T* [(was)-362.2(from)-362.7(8.9)-362.7(to)-359.4(6,500)-169.1(ng/mL,)-362.8(samples)-362.3(were)-364.7(diluted)-360.6(before)]TJ 0 -1.1174 TD [(analysis.)-296.7(Western)-294.4(blotting)-297.3(was)-293.1(used)-287.6(to)-296.1(conrm)-291(the)-292.6(165-kDa)]TJ 0 -1.1116 TD [(MAM)-386.1(subunit)-382.2(and)-384.6(180-kDa)-384.1(MUG1)-387.2(subunit.)-385.6(A)-382.1(Hyg)-384.3(qPCR)]TJ T* [(assay)-232.1(as)-227.8(a)-232.6(TaqMan)-229.9(qPCR)-230.9(targeting)-231.5(the)-229.2(selection)-232.5(cassette)-232.2(as)-227.8(a)]TJ 0 -1.1174 TD [(surrogate)-242.5(was)-241.3(used)-241.5(for)-239.4(genotyping)-242.8(us)21(in)20.7(g)-225.7(t)0(h)15(e)-226.9(fo)20.9(ll)20.6(ow)20(in)15(g)-225.7(M)0(A)19.1(M)]TJ 0 -1.1116 TD [(pr)15.1(im)19.5(er)-654.2(pr)20.9(ob)20.8(e)-664.6(s)0(e)14.1(q)0(u)20.8(e)0(n)19.7(c)0(e)18.5(s)0(:)-653(h)0(y)15.1(g)0(q)20.8(F)0(8)21(2)0(1)20.8(:)0(5)]TJ /F8 1 Tf 15.8507 0 TD ()Tj /F3 1 Tf .2419 0 TD [(CC)18.8(GC)18.9(AA)19.1(GG)19.1(AA)19.1(TC)]TJ -16.0926 -1.1116 TD [(GG)19.1(TC)18.6(AA)13.3(T3)]TJ /F8 1 Tf 5.1953 0 TD ()Tj /F3 1 Tf .2361 0 TD -.0208 Tc [(,)-680.8(h)-20.8(yg)-20.8(qR)-20.8(8)-6.8(7)-20.8(8:)-678.6(5)]TJ /F8 1 Tf 6.4278 0 TD 0 Tc ()Tj /F3 1 Tf .2419 0 TD [(GA)19.1(TC)18.6(AG)19.1(CA)18.9(AT)18.8(CG)18.9(CG)18.9(CA)18.9(TA)]TJ -12.1011 -1.1174 TD [(TG)18.8(3)]TJ /F8 1 Tf 1.8028 0 TD ()Tj /F3 1 Tf .2419 0 TD -.0208 Tc [(,)-749.9(h)-20.8(y)-5.7(g)-20.8(qp)-20.8(ro)-20.8(be)-20.8(:)-744.3(5)]TJ /F8 1 Tf 6.6755 0 TD 0 Tc ()Tj /F3 1 Tf .9791 0 TD [([V)14.2(ic)19.6(]C)19.8(AC)18.9(TA)18.8(CA)18.9(TG)18.8(GC)18.9(GT)18.8(GA)19.1(TT)18.5([M)]TJ -9.6993 -1.1116 TD [(GB)18.9(]3)]TJ /F8 1 Tf 2.1829 0 TD ()Tj /F3 1 Tf .2361 0 TD [(,)-274.1(a)0(n)19.7(d)-266(ap)13.9(ob)-255.6(qP)15.2(CR)-257.7(as)19.9(sa)14.1(y)-266(a)0(s)-262.4(a)0(n)-262.5(e)0(n)19.7(d)0(o)20.8(g)0(e)19.7(n)0(o)15.1(u)0(s)-255.4(c)0(o)13.9(n)0(t)20.7(r)0(o)20.9(l)-271.9(us)21(in)20.7(g)]TJ -2.4191 -1.1116 TD [(mA)18.7(po)20.8(bq)15.1(Fe)19.8(26)20.8(:5)]TJ /F8 1 Tf 6.1629 0 TD ()Tj /F3 1 Tf .2419 0 TD [(CG)18.9(TG)18.8(GG)19.1(CT)18.6(CC)18.8(AG)19.1(CA)18.9(TT)18.5(CT)18.6(A3)]TJ /F8 1 Tf 13.1206 0 TD ()Tj /F3 1 Tf .2419 0 TD .8271 Tc [(,m)827.1(A)845.8(p)827.1(o)847.9(b)827.1(q)]TJ -19.7673 -1.1174 TD 0 Tc [(Re)18.6(26)15.1(:5)]TJ /F8 1 Tf 2.8395 0 TD ()Tj /F3 1 Tf .2361 0 TD [(CT)18.6(GC)18.9(CT)18.6(TT)18.5(GC)18.9(GT)18.8(CC)18.8(TT)18.4(GA)19.1(G)-480(3)]TJ /F8 1 Tf 13.4028 0 TD ()Tj /F3 1 Tf .2419 0 TD -.0203 Tc [(,)-496(m)-20.3(Ap)-20.3(ob)-20.3(qp)-20.3(e)-6.4(2)-20.3(6:)-493.8(5)]TJ /F8 1 Tf 7.3206 0 TD 0 Tc ()Tj /F3 1 Tf -24.041 -1.1116 TD [([6)15.1(Fa)19.8(m])-815.5(AG)19.1(CC)18.8(AA)19.1(TG)18.8(GT)18.8(CG)18.9(GG)13.3(C)-825.8([)0(M)20(G)0(B)18.9(])-830.5(3)]TJ /F8 1 Tf 18.9955 0 TD ()Tj /F3 1 Tf 1.0771 0 TD [(se)19.9(qu)20.8(en)19.7(ce)18.5(s,)]TJ -20.0726 -1.1116 TD [(re)14(sp)21(ec)18.5(ti)20.6(ve)19.7(ly)20.7(.)-481.5(T)0(h)19.6(e)-486.1(A2)20(M)-480(c)0(o)19.7(l)0(o)20.7(n)0(y)-474.5(w)0(a)18.8(s)-479(ma)18.4(in)20.7(ta)13.8(in)20.7(ed)-469.9(at)-475.8(Ch)19.8(ar)19.7(le)19.5(s)]TJ T* [(Ri)19.7(ve)13.9(rs)-272.7(La)18.5(bo)20.8(ra)14(to)20.7(ri)20.7(es)-279.6(\(H)20(ol)20.7(li)20.6(st)20.9(er)14(,)-285.7(C)0(A)18.9(\))-283.3(be)19.7(fo)15.1(re)-274(de)19.7(li)20.6(ve)19.7(ry)-278.6(at)-280(IO)20(NI)20(S)]TJ 0 -1.1174 TD [(Ph)15.2(ar)19.7(ma)18.4(ce)18.5(ut)20.7(ic)19.6(al)19.5(s.)]TJ /F1 1 Tf 8.9663 0 0 8.9663 59.7543 396.3968 Tm [(In)-336.7(vivo)]TJ /F10 1 Tf 3.2753 0 TD [(study)-333.9(design)]TJ /F3 1 Tf 9.843 0 0 9.843 69.7323 379.9558 Tm [(All)-223.3(animals)-224.4(and)-223.3(procedures)-227.4(conducted)-226.6(in)-221.2(the)-223.5(study)-224.3(were)-220.7(in)]TJ -1.0137 -1.1174 TD [(compliance)-506.7(and)-505.6(approved)-500.7(by)-503.3(the)-499.9(IONIS)-508.1(Pharmaceuticals)]TJ 0 -1.1116 TD [(Institutional)-315.5(Animal)-309.6(Care)-313(and)-309.7(Use)-310.4(Committee)-315.6(\(Protocol:)-311.9(P-)]TJ T* [(0214-100019)-6.3(\).)-355.8(A)-353.3(total)-358.4(of)-359.3(40)-353.5(mixed)-359.4(gender)-360.2(C57BL/6)-356.7(mice,)]TJ 0 -1.1174 TD [(including)-339.8(20)-330.5(WT/WT)-335.1(and)-338.5(20)-330.5(MAM/MUG1)-336.8(DKO)-334.2(homozy-)]TJ 0 -1.1116 TD [(gous)-441.9(mice)-440.1(aged)-438.7(610)-442.1(weeks)-440.5(and)-442.2(weighing)-437.3(1825)-166.8(g,)-442.3(were)]TJ T* [(used.)-291(Baseline)-289.9(characteristics)-288.5(at)-285.7(study)-287.7(initiation)-289.4(are)-287.8(listed)-284.4(in)]TJ T* [(Ta)18.5(bl)14.9(e)-278.7(1)0(.)-275.2(D)0(o)20(s)0(i)20.9(n)0(g)-272.9(s)0(o)21(l)0(u)20.7(t)0(i)20.6(o)0(n)15.1(s)-277.4(of)-272.9(IO)20(N-)14.2(35)20.8(33)20.8(82)-272.9(a)-278.7(5)0(-)15.1(1)0(0)20.8(-)0(5)-272.9(m)0(e)18.4(t)0(h)20.7(o)0(x)20.8(y)0(-)]TJ 0 -1.1174 TD .0111 Tc [(eth)4.2(y)-1.5(l)-543.1(\()-82.1(MOE\))-548.7(ASO)-543.8(t)4.1(arg)4.2(e)-2.7(t)4.1(i)-1.6(ng)-542.9(S)4.4(R)-2.5(B1)-542.9(wer)4.3(e)-544.1(fo)4.2(rmulated)-542.9(in)]TJ 0 -1.1116 TD [(steri)4(l)-1.7(e)-279.2(s)-1.4(alin)4.1(e)-279.2(a)-2.8(t)-278.2(1)-1.6(,)-274.7(3)-1.6(,)-280.4(6)4.1(,)-280.4(a)-2.8(n)4.1(d)-278.1(12)-168.6(mg)4.1(/mL.)]TJ 1.0137 -1.1116 TD 0 Tc [(ION-353382)-398.6(was)-391(administered)-404(as)-394.8(a)-393.9(single)-393.7(subcutaneous)]TJ -1.0137 -1.1174 TD [(dose)-253(to)-255.8(the)-252.3(nape)-254.4(of)-249.8(the)-252.3(neck)-254.4(at)-251.2(5,)-252.2(15,)-253.3(30,)-247.5(and)-257.9(60)-163.5(mg/kg)-254.5(using)]TJ 0 -1.1116 TD [(saline)-187.5(as)-181.7(a)-180.8(dosing)-185.1(vehicle)-184.2(control)-181.9(with)-184.1(a)-186.6(dose)-178.2(volume)-187.7(of)-180.7(5)-168.1(mL/)]TJ T* [(kg.)-414.6(A)-416.7(total)-416(of)-411.1(10)-411.1(treatment)-418.2(groups)-415.3(were)-416.5(used.)-417.7(Mice)-416.7(were)]TJ 0 -1.1174 TD [(fasted)-285.3(overnight)-287.8(before)-285.3(dosing,)-280.7(while)-284.3(allowed)-287.6(water)]TJ /F7 1 Tf 21.3339 0 TD [(ad)-284.4(libi-)]TJ -21.3339 -1.1116 TD (tum)Tj /F3 1 Tf 1.8143 0 TD [(continuously,)-311.8(and)-315.5(fed)-309.7(3)-168.1(h)-312.1(postdose)-309.2(while)-313.1(maintained)-315.6(in)]TJ -1.8143 -1.1116 TD [(standard)-339.3(cages.)-340.5(Following)-339.3(72)-163.5(h)-335.2(after)-342(dosing,)-338.3(mice)-336.4(were)-335.9(eu-)]TJ 0 -1.1174 TD [(thanized)-335.1(by)-330.5(terminal)-329.5(cardiac)-335(puncture)-328(and)-332.8(cervical)-330.5(disloca-)]TJ 0 -1.1116 TD [(tion,)-347.9(with)-351.1(whole)-347.5(blood)-351.2(collected)-349(and)-350(stored)-347.5(into)-350.2(K)]TJ 7.3823 0 0 6.5614 265.6629 181.0204 Tm (2)Tj 9.843 0 0 9.843 269.3479 182.6645 Tm (EDTA-)Tj -21.2936 -1.1116 TD [(containing)-445.7(tubes)-444.3(followed)-443.1(by)-445.7(centrifugation)-445.6(at)-441.2(2,000)]TJ /F7 1 Tf 22.1864 0 TD (g)Tj /F3 1 Tf .9388 0 TD (for)Tj -23.1252 -1.1116 TD [(10)-169.2(min)-292.6(at)-297.2(4)]TJ /F8 1 Tf 4.5502 0 TD ()Tj /F3 1 Tf .3974 0 TD [(C)-295.9(t)0(o)-296.1(s)0(e)19.9(p)0(a)19.7(r)0(a)19.7(t)0(e)-274.2(p)0(l)20.7(a)0(s)14.1(m)15(a.)-276.4(Li)19.5(ve)19.7(r,)-275.2(ki)14.9(dn)20.8(ey)19.7(s,)-275(lu)20.7(ng)20.8(,)-285.7(m)0(u)19.6(s)0(-)]TJ 20.5622 57.3379 TD [(cl)19.5(e,)-224.6(an)19.7(d)-237.2(h)0(e)19.7(a)0(r)19.7(t)-237.4(fr)20.9(om)-228.1(ea)18.5(ch)-228(mi)19.5(ce)-229.1(we)18.8(re)-228(ha)19.7(rv)20.9(es)19.9(te)19.6(d)-237.2(a)0(n)19.7(d)-237.2(a)19.8(sh)-226.6(fr)20.9(oz)19.7(en)]TJ 0 -1.1174 TD [(in)-261.5(li)20.6(qu)20.8(id)-261.5(ni)20.7(tr)20.7(og)20.8(en)-262.5(an)19.7(d)-271.8(s)0(t)20.9(o)0(r)20.9(e)0(d)-262.6(a)0(t)]TJ /F8 1 Tf 12.4986 0 TD (-)Tj /F3 1 Tf .5472 0 TD (80)Tj /F8 1 Tf .9791 0 TD ()Tj /F3 1 Tf .3859 0 TD -.0193 Tc [(C)-286.4(b)-19.3(ef)-19.3(or)-19.3(e)-276.1(a)-19.3(na)-19.3(l)-5.5(y)-19.3(si)-19.3(s.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 310.8472 692.277 Tm 0 Tc [(Plasma)-333.7(and)-335.7(tissue)-330.8(exposure)-333(kinetics)-333.7(in)-336.5(DKO)-332.6(mice)]TJ /F3 1 Tf 9.843 0 0 9.843 320.8251 675.8361 Tm [(Plasma)-269.1(C)]TJ 7.3823 0 0 6.5614 358.5259 674.192 Tm (trough)Tj 9.843 0 0 9.843 380.466 675.8361 Tm [(levels)-273.9(at)-268.4(72)-169.2(h)-266(were)-272.5(evaluated)-274(for)-268.2(both)-269.5(WT/)]TJ -7.0729 -1.1116 TD [(WT)-253.3(and)-252.1(HO/HO)-256.8(groups)-254.1(using)-253.1(enhanced)-261.1(chemiluminescence)]TJ 0 -1.1174 TD [(\(ECL\)-ELISA.)-430.9(A)-428.2(calibration)-430.8(curve)-428.3(was)-431.4(setup)-427.1(from)-426(0.5)-431.8(to)]TJ 0 -1.1116 TD [(100)-164.6(ng/mL.)-316.8(Stock)-317.7(capture)-322.3(probe)-311.9(for)-320(ION-353382,)-315.6(5)]TJ /F8 1 Tf 21.0287 0 TD ()Tj /F3 1 Tf .2534 0 TD (BioTeg)Tj -21.2821 -1.1116 TD (AeAkGeGeAkAeGeTk)Tj 7.3823 0 0 6.5614 403.2566 636.3778 Tm (m)Tj 9.843 0 0 9.843 408.9825 632.0125 Tm [(CeAe,)-495.9(k)]TJ /F8 1 Tf 3.6862 0 TD (=)Tj /F3 1 Tf .72 0 TD [(cEt)-489.6(BNA)-489.9(\(3\);)-488.3(e)]TJ /F8 1 Tf 6.975 0 TD (=)Tj /F3 1 Tf .72 0 TD (MOE)Tj -22.0712 -1.1174 TD [(\(7\),)-294.7(was)-293.1(diluted)-297.2(to)-290.3(25)-169.2(nmol)-293.8(in)-296.1(10)]TJ /F8 1 Tf 13.3107 0 TD ()Tj /F3 1 Tf .8467 0 TD [(SSPE)-293.1(buffer,)-299.1(and)-292.4(100)]TJ /F9 1 Tf 8.9679 0 TD (m)Tj /F3 1 Tf .5529 0 TD (L)Tj -23.6782 -1.1116 TD [(was)-183.7(added)-186.4(to)-180.9(25)]TJ /F9 1 Tf 6.4451 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-186.6(o)0(f)-180.7(each)-186.4(plasma)-188.7(sample)-182.9(and)-183(standard)-189.6(into)-183.2(a)]TJ -6.9923 -1.1116 TD [(96-well)-401.6(PCR)-402.6(plate,)-403.2(sealed,)-405.1(and)-407.6(heated)-401.9(at)-400.9(70)]TJ /F8 1 Tf 18.529 0 TD ()Tj /F3 1 Tf .3974 0 TD [(C)-399.5(for)-400.7(30)-169.2(min)]TJ -18.9264 -1.1174 TD [(followed)-183.9(by)-186.5(cooling)-187.7(at)-187.8(room)-184.2(temperature)-191(21)]TJ /F8 1 Tf 17.331 0 TD ()Tj /F3 1 Tf .3917 0 TD [(C)-186.4(for)-187.5(15)-163.5(min)-189(and)]TJ -17.7226 -1.1116 TD [(cooled)-343.1(to)-342.1(6)]TJ /F8 1 Tf 4.6423 0 TD ()Tj /F3 1 Tf .3917 0 TD [(C)-341.9(for)-343.1(15)-169.2(min)-338.7(to)-342.1(complete)-347.9(hybridization.)-343.1(At)-343(the)]TJ -5.034 -1.1116 TD [(same)-370.6(time,)-367.6(an)-372(MSD)-367.8(gold)-373.2(streptavidin-coated)-372.7(96-well)-372.8(plate)]TJ T* [(was)-298.9(blocked)-298.2(using)-293.4(1.5)-166.9(g)-294.8(o)0(f)-295.9(blocker)-298.1(A)-295.7(dissolved)-298.9(in)-296.1(50)-169.2(mL)-298.4(of)]TJ 0 -1.1174 TD [(PBS)-297.8(with)-305(150)]TJ /F9 1 Tf 5.8173 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-301.8(added)-301.6(to)-301.8(each)-307.4(well)-300.4(and)-304(incubated)-301.7(at)-303(21)]TJ /F8 1 Tf 16.8587 0 TD ()Tj /F3 1 Tf .3974 0 TD (C)Tj -23.6263 -1.1116 TD [(for)-343.1(60)-163.5(min.)-347.9(Next,)-344.1(the)-344.4(MSD)-339(plate)-347.9(was)-345(rinsed)-341.7(for)-343.1(two)-344.1(cycles)]TJ T* [(with)-270.5(10)-169.2(mM)-269.3(phosphate)-271.4(buffer)-272.6(pH)-273.8(7.4,)-268.2(150)-170.3(mM)-269.3(NaCl,)-276(0.05%)]TJ 0 -1.1174 TD [(Tween-20)-283.9(\(PBS-T\))-280.2(washing)-286.1(buffer.)]TJ 1.0137 -1.1116 TD [(Samples)-339.3(from)-333.9(the)-338.7(PCR)-339.3(plate)-336.4(were)-341.6(mixed)-336.3(68)-337.4(times,)-339.7(and)]TJ -1.0137 -1.1116 TD (50)Tj /F9 1 Tf 1.1635 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-445.8(was)-448.6(transferred)-453.2(to)-445.8(the)-448.1(MSD)-448.4(plate)-451.6(in)-445.8(duplicate)-451.5(and)]TJ -1.7164 -1.1174 TD [(allowed)-253.1(to)-255.8(immobilize)-252.5(on)-255.6(the)-252.3(plate)-255.8(using)-253.1(shaking)-250.7(at)-256.9(500)-164.6(rpm)]TJ 0 -1.1116 TD [(at)-245.4(21)]TJ /F8 1 Tf 1.9698 0 TD ()Tj /F3 1 Tf .3974 0 TD [(C)-244(for)-245.1(30)-169.2(min.)-244.2(Plates)-245(were)-249.5(then)-247.6(rinsed)-243.8(for)-245.1(two)-246.2(cycles.)-243.9(A)]TJ -2.3672 -1.1116 TD [(preheated)-688.5(detector)-686.4(probe)-686.3(for)-688.6(ION-353382,)-690(5)]TJ /F8 1 Tf 19.871 0 TD ()Tj /F3 1 Tf .2534 0 TD (-TkGxAe-)Tj 7.3823 0 0 6.5614 310.8472 450.0849 Tm (m)Tj 9.843 0 0 9.843 316.6299 445.7196 Tm (CxTkGeAfAfGe)Tj 7.3823 0 0 6.5614 382.7338 450.0849 Tm (m)Tj 9.843 0 0 9.843 388.5164 445.7196 Tm (Ck-[Spacer]-\(NH2\)-3)Tj /F8 1 Tf 8.6684 0 TD ()Tj /F3 1 Tf .2534 0 TD .3145 Tc (,k)Tj /F8 1 Tf 1.2326 0 TD 0 Tc (=)Tj /F3 1 Tf .7142 0 TD [(cEt)-322.6(BNA)-317.1(\(3\);)]TJ -18.7594 -1.1174 TD (e)Tj /F8 1 Tf .6105 0 TD (=)Tj /F3 1 Tf .72 0 TD [(MOE)-374.9(\(3\);)-373.1(f)]TJ /F8 1 Tf 4.913 0 TD (=)Tj /F3 1 Tf .72 0 TD (2)Tj /F8 1 Tf .5011 0 TD .3721 Tc (-)Tj /F3 1 Tf 1.5436 0 TD 0 Tc [(F)-375.3(\(2\);)-373.1(x)]TJ /F8 1 Tf 3.4155 0 TD (=)Tj /F3 1 Tf .72 0 TD [(deoxy)-369.5(\(2\),)-375.3(was)-373.8(prepared)-380.9(at)]TJ -13.1436 -1.1116 TD [(2)-168.1(nmol,)-228.1(and)-234.9(50)]TJ /F9 1 Tf 6.0592 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-232.7(o)0(f)-226.8(was)-235.5(added)-238.2(to)-232.7(each)-232.5(well)-231.3(incubated)-238.3(using)]TJ -6.6121 -1.1116 TD [(shaking)-227.7(at)-228.1(500)-164.6(rpm)-229.1(at)-228.1(21)]TJ /F8 1 Tf 9.7627 0 TD ()Tj /F3 1 Tf .3974 0 TD [(C)-226.8(for)-227.9(30)-163.5(min.)-227(Plates)-233.5(were)-226.4(rinsed)-232.3(for)]TJ -10.1601 -1.1174 TD [(four)-367.2(cycles,)-370.6(and)-373.1(150)]TJ /F9 1 Tf 8.6453 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-370.9(o)0(f)-365(MSD)-373.5(read)-369.6(buffer)-370.5(was)-373.8(added)-370.7(to)]TJ -9.1982 -1.1116 TD [(each)-203.7(well.)-206(Plates)-204.7(were)-203.4(read)-208.3(on)-203.8(a)-198.1(Sector)-210.5(PR)-198.9(2400)-206(MSD)-200.7(system)]TJ T* [(\()-81.7(Meso)-282.7(Sale)-283.2(Discovery\).)]TJ 1.0137 -1.1174 TD [(For)-423.6(tissue)-433.9(exposure)-431.4(kinetics,)-429.5(the)-430.8(liver)-427.4(and)-430.7(kidney)-428.4(were)]TJ -1.0137 -1.1116 TD [(weighed)-316.3(to)-313.4(50)-169.2(mg)-308.7(and)-315.5(diluted)-314.5(in)-313.4(450)]TJ /F9 1 Tf 15.1941 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-313.3(o)0(f)-313.2(homogenization)]TJ -15.747 -1.1116 TD [(buffer)-289.9(\(20)-164.5(mM)-292.3(Tris)-287.7(pH)-291.1(8,)-286.8(10)-163.5(mM)-292.3(EDTA,)-288.4(0.1)-166.9(M)-290(NaCl,)-287.5(0.5%)]TJ 0 -1.1174 TD [(NP40\))-184.7(and)-188.8(broken)-186.3(up)-186.5(by)-186.5(homogenization.)-191(A)-186.3(calibration)-188.9(curve)]TJ 0 -1.1116 TD [(was)-494.7(prepared)-496.1(from)-489.4(0.05)-496.3(to)-491.9(100)]TJ /F9 1 Tf 13.6678 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(mol)-494.2(using)-495(ION-353382.)]TJ -14.2207 -1.1116 TD [(Samples)-460.3(were)-456.8(basied)-459.1(with)-460.5(300)]TJ /F9 1 Tf 13.7311 0 TD (m)Tj /F3 1 Tf .5529 0 TD .4573 Tc [(Lo)457.3(fN)457.3(H)]TJ 7.3823 0 0 6.5614 488.8062 312.5479 Tm 0 Tc (4)Tj 9.843 0 0 9.843 492.5479 314.192 Tm [(OH,)-456.6(extracted)]TJ -18.4599 -1.1116 TD [(with)-184.1(800)]TJ /F9 1 Tf 3.6344 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-186.6(o)0(f)-186.5(phenol/chloroform/isoamyl)-195.3(alcohol)-183.1(\(25:24:1\),)]TJ -4.1815 -1.1174 TD [(and)-234.8(centrifuged)-234.7(at)-233.9(13,000)]TJ /F7 1 Tf 10.1947 0 TD (g)Tj /F3 1 Tf .7372 0 TD [(for)-227.9(4)-168.1(min)-235(to)-232.7(separate)-238(aqueous)-234.5(and)]TJ -10.9319 -1.1116 TD [(organic)-315.4(layers.)-323.3(Aqueous)-320.6(supernatants)-321.8(were)-318.6(removed)-316.5(and)-321.2(an)]TJ T* [(additional)-284.6(back)-277.4(extraction)-285.6(was)-281.6(performed.)]TJ 1.0137 -1.1174 TD [(Following)-494.8(the)-494.2(liquidliquid)-498.9(extraction,)-496.4(solid)-495.1(phase)-497.2(ex-)]TJ -1.0137 -1.1116 TD [(traction)-293.7(\(SPE\))-294.3(was)-293.1(performed.)-293.3(SPE)-292.2(plates)-297(were)-289.8(equilibrated)]TJ T* [(with)-345.4(2)-168.1(m)0(L)-344.4(o)0(f)-347.7(acetonitrile)-352.6(followed)-345.1(by)-347.8(2)-168.1(m)0(L)-344.4(o)0(f)-347.7(1)-168.1(M)-347.6(triethy-)]TJ 0 -1.1174 TD [(lammonium)-239.7(bicarbonate)-235.9(\(TEAB\).)-244.7(Samples)-235.7(were)-238(loaded)-239.4(onto)]TJ 0 -1.1116 TD [(the)-229.2(cartridges)-233.4(followed)-235.7(by)-226.8(a)-232.6(rinse)-231.2(with)-235.9(2)-162.4(m)0(L)-235(o)0(f)-226.8(0.1)-166.9(M)-232.4(TEAB,)]TJ T* .1681 Tc [(2m)168.1(L)-61.2(o)168.1(f)-64.5(H)]TJ 7.3823 0 0 6.5614 350.9857 202.9606 Tm 0 Tc (2)Tj 9.843 0 0 9.843 354.6707 204.6047 Tm [(O,)-235.8(2)-162.4(m)0(L)-235(o)0(f)-232.6(2)0(%)-233.6(N)0(H)]TJ 7.3823 0 0 6.5614 429.1086 202.9606 Tm (4)Tj 9.843 0 0 9.843 432.8503 204.6047 Tm [(OH)-228.6(\(in)-233.8(5%)-233.7(acetonitrile,)-240.8(0.1)-166.9(M)]TJ -12.3949 -1.1174 TD [(TEAB\),)-554.6(and)-557.4(2)-168.1(m)0(L)-551.8(o)0(f)-555.1(10%)-557.3(acetonitrile)-559.9(in)-555.3(0.1)-166.9(M)-554.9(TEAB.)]TJ 0 -1.1116 TD [(Samples)-489.1(were)-497.1(eluted)-487.2(with)-495.1(1.5)-166.9(mL)-488.4(of)-491.7(70%)-488.2(acetonitrile)-496.6(in)]TJ T* [(0.1)-166.9(M)-359.1(TEAB)-365.8(and)-361.6(run)-366.1(through)-359.1(a)-365.1(protein)-360.4(precipitation)-369.8(plate.)]TJ T* [(Finally,)-669.1(samples)-667.6(were)-669.9(dried)-669.1(down)-667.6(under)-669(nitrogen)-666.8(and)]TJ ET 59.754 124.894 490.167 .22675 re f 59.754 77.499 490.167 .22675 re f 59.754 106.242 490.167 .22675 re f BT /F6 1 Tf 9.845 0 0 9.845 181.1338 130.5638 Tm (Table)Tj /F3 1 Tf 3.0002 0 TD (1.)Tj /F6 1 Tf 1.2496 0 TD [(Baseline)-332.4(Characteristics)-339.1(at)-330(Study)-333.8(Initiation)]TJ /F7 1 Tf -16.5788 -1.8427 TD [(Group)-3460.7(Number)-337(per)-332.2(subtype)-2664(Age)-333.5(\(weeks\))]TJ /F8 1 Tf 22.1301 0 TD ()Tj /F9 1 Tf .7141 0 TD (s)Tj /F7 1 Tf .668 0 TD (x)Tj /F3 1 Tf 7.3837 0 0 6.5625 295.6534 116.8441 Tm (a)Tj /F7 1 Tf 9.845 0 0 9.845 325.1338 112.422 Tm [(Gender)-331.4(\(n\))-2657.7(Alpha-2-Macroglobulin)-341.3(\(mg/mL\))]TJ /F8 1 Tf 20.6617 0 TD ()Tj /F9 1 Tf .7198 0 TD (s)Tj /F7 1 Tf .668 0 TD (x)Tj /F3 1 Tf 7.3837 0 0 6.5625 546.6329 116.8441 Tm (a)Tj 9.845 0 0 9.845 59.7543 93.7701 Tm [(WT/WT)-6300.1(20)-8006.4(6.6)]TJ /F8 1 Tf 20.1261 0 TD ()Tj /F3 1 Tf .7141 0 TD [(0.36)-4768.7(11)-169(M,)-333.4(9)-335(F)-7435.1(3.470)]TJ /F8 1 Tf 20.3968 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.6990)Tj -41.9568 -1.0135 TD [(HO/HO)-6550.1(20)-8006.4(6.8)]TJ /F8 1 Tf 20.1261 0 TD ()Tj /F3 1 Tf .7141 0 TD [(0)-5684.7(1)0(0)-169(M)0(,)-333.4(1)0(0)-169(F)-7435.1(0.003)]TJ /F8 1 Tf 20.3968 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.0004)Tj 7.3837 0 0 6.5625 499.8613 88.1575 Tm (b)Tj 6.5633 0 0 5.8334 67.748 69.5622 Tm (a)Tj 8.7511 0 0 8.7511 70.696 65.6504 Tm [(Standard)-333.5(deviation)-331.4(of)-333.1(the)-333.3(average.)]TJ 6.5633 0 0 5.8334 67.748 60.6047 Tm (b)Tj 8.7511 0 0 8.7511 71.0362 56.6929 Tm [(Statistically)-334.1(signicant,)]TJ /F7 1 Tf 9.8342 0 TD (P)Tj /F8 1 Tf .7839 0 TD (<)Tj /F3 1 Tf .7191 0 TD (0.001.)Tj /F4 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(PK/PD)-340.1(OF)-331.2(ION-353382,)-332.4(A)-337.9(MODEL)-333.5(ASO:)-334.7(IN)-335.1(WT)-335.9(AND)-330.9(DKO)-337.5(MICE)-23255.2(225)]TJ ET endstream endobj 88 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 62.022 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(reconstituted)-237(to)-232.7(140)]TJ /F9 1 Tf 8.0981 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-232.7(with)-224.4(100)]TJ /F9 1 Tf 4.5156 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(mol)-223.5(EDTA)-221.6(prior)-224.4(for)-222.1(liquid)]TJ -13.7196 -1.1174 TD [(chromatographymass)-275.4(spectrometry)-277.1(\(LC-MS\))-275.5(analysis.)]TJ 1.0137 -1.1116 TD [(An)-256.5(Ag)14.2(il)14.8(en)13.9(t)-266.2(1)0(1)15.1(0)0(0)15.1(/)0(1)15(2)0(0)15.1(0)-266(HP)14.4(LC)-257.9(sy)15.3(st)15.1(em)-258(co)13.9(ns)15.3(is)15.1(ti)14.8(ng)-261.4(of)-255.6(a)-267.2(1)0(,)12.7(1)0(0)15.1(0)]TJ -1.0137 -1.1116 TD [(qu)15.1(at)13.8(er)13.9(na)13.9(ry)-238.3(pu)15.1(mp)13.8(,)-245.3(c)0(o)13.9(l)0(u)15(m)0(n)-239.6(o)0(v)15.1(e)0(r)14(,)-251.1(an)19.7(d)-248.8(a)0(u)13.9(t)0(o)15(s)0(a)14.1(m)0(p)13.9(l)0(e)13.8(r)-248.7(co)13.9(up)20.8(le)13.8(d)-248.8(t)0(o)-244.2(a)]TJ T* [(si)15.1(ng)15.1(le)-504.6(qu)15.1(ad)19.7(ru)15.1(po)15.1(le)-504.6(ma)12.7(ss)-502.9(sp)15.3(ec)12.8(tr)15(om)19.6(et)13.8(er)-504.4(\(A)14.2(gi)15(le)13.8(nt)-497.7(61)15.1(30)15.1(;)-513.8(W)0(i)18.4(l)0(-)]TJ 0 -1.1174 TD [(mi)13.7(ng)15.1(to)15(n,)-355.9(DE)13(\))-363.9(w)0(a)13(s)-363.8(us)15.3(ed)13.9(.)-360.5(A)0(n)-360.2(X)0(B)13.2(r)0(i)15(d)0(g)15.1(e)-365.1(co)13.9(lu)15(mn)-354.8(\(5)15.1(0)]TJ /F8 1 Tf 20.3894 0 TD ()Tj /F3 1 Tf .7142 0 TD [(2.)18.5(1)-162.4(m)0(m)18.4(,)]TJ -21.1036 -1.1116 TD [(2.)12.7(5)]TJ /F9 1 Tf 1.3938 0 TD (m)Tj /F3 1 Tf .5414 0 TD [(m\))-377.8(wa)13(s)-386.8(u)0(s)15.3(e)0(d)-377.7(f)0(o)15.1(r)-387(ch)19.7(ro)15.1(ma)12.7(to)15(gr)15.1(ap)13.9(hi)14.9(c)-382.4(s)0(e)14.1(p)0(a)13.9(r)0(a)14(t)0(i)14.8(o)0(n)-376.6(\()0(W)18.6(a)0(t)13.8(e)0(r)14(s)0(\))15.3(.)]TJ -1.9353 -1.1116 TD [(Th)13.9(e)-232.6(c)0(o)13.9(l)0(u)20.7(m)0(n)-228.1(t)0(e)19.5(m)0(p)13.9(e)0(r)14(a)0(t)13.8(u)0(r)15.1(e)-232.6(wa)13(s)-231.3(m)0(a)18.4(i)0(n)15(t)0(a)13.8(i)0(n)15(e)0(d)-222.2(a)0(t)-222.4(5)0(5)]TJ /F8 1 Tf 18.264 0 TD ()Tj /F3 1 Tf .3917 0 TD .2325 Tc [(Cw)232.5(i)252.3(t)232.5(h)5.5(m)232.5(o)246.3(b)232.5(i)253.2(l)232.5(e)]TJ -18.6557 -1.1174 TD 0 Tc [(ph)15.1(as)14.1(e)-186.6(A)-186.3(co)19.7(ns)15.3(is)15.1(ti)14.8(ng)-180.7(of)-175(5)-156.6(m)0(M)-177.1(T)0(r)13.9(i)0(B)13.9(u)0(t)14.9(A)0(A)-176.7(i)0(n)-180.9(2)0(0)15.1(%)-180.7(ac)12.8(et)13.8(on)15.1(it)14.8(ri)15(le)-176.3(an)13.9(d)]TJ 0 -1.1116 TD [(mo)13.8(bi)15(le)-262.7(ph)20.8(as)14.1(e)-273(B)-267.1(co)13.9(ns)15.3(is)15.1(ti)14.8(ng)-261.4(of)-261.4(5)-156.6(m)0(M)-263.5(T)0(r)13.9(i)0(B)13.9(u)0(t)14.9(A)0(A)-257.4(i)0(n)-261.5(9)0(0)15.1(%)-272.9(ac)18.5(et)13.8(o-)]TJ T* [(ni)15(tr)15(il)14.8(e.)-190(A)-203.6()0(o)15.2(w)-197.8(ra)14(te)-193.6(of)-192.2(0.)18.5(30)-152(mL)12.7(/m)13.7(in)-186.6(wa)13(s)-202.5(u)0(s)15.3(e)0(d)-193.4(a)0(t)-193.6(2)0(2)20.8(%)-203.7(B)-198(i)0(n)15(i)0(t)14.8(i)0(a)13.8(l)0(l)14.8(y)]TJ 0 -1.1174 TD [(wh)14.2(il)14.8(e)-319(r)0(a)14(m)0(p)13.8(i)0(n)15(g)-317.9(to)-313.3(80)15.1(%)-318.9(t)0(o)-313.4(6)-156.6(mi)13.7(n)-317.9(a)0(n)13.9(d)-323.6(he)19.7(ld)-313.3(fo)15.1(r)-323.6(1)0(.)18.5(5)-162.4(mi)19.5(n;)-313.4(ov)15.1(er)-314.4(a)]TJ 0 -1.1116 TD [(pe)13.9(ri)15(od)-175(of)-175(0.)18.5(2)-162.4(m)0(i)13.7(n)-179.6(th)15(e)-186.6(g)0(r)15.1(a)0(d)19.7(i)0(e)13.8(n)0(t)-175.1(r)0(e)14(t)0(u)15(r)0(n)15.1(e)0(d)-176.2(t)0(o)-175.1(i)0(n)15(i)0(t)14.8(i)0(a)13.8(l)-179.8(co)13.9(nd)15.1(it)14.8(io)15(ns)-174.8(an)13.9(d)]TJ T* [(wa)13(s)-369.5(h)0(e)13.9(l)0(d)-359.4(f)0(o)15.1(r)-369.7(on)15.1(e)-370.9(a)0(d)13.9(d)0(i)14.9(t)0(i)14.8(o)0(n)15.1(a)0(l)-360.6(m)0(i)13.7(n)0(u)15.1(t)0(e)19.6(.)-372(Ne)13(ga)13.9(ti)14.8(ve)-360.5(po)15.1(la)13.8(ri)15(ty)-359.4(el)13.8(ec)12.8(-)]TJ T* [(tr)15(os)15.3(pr)15.1(ay)-181.9(io)15(ni)15(za)12.8(ti)20.6(on)-186.5(wa)18.8(s)-191(u)0(s)15.3(e)0(d)-181.9(w)0(i)14.1(t)0(h)-180.9(a)-192.3(sc)19.9(an)-181.9(ti)14.8(me)-183.1(of)-180.7(2)15.1(8)-162.4(m)0(i)19.5(n)-191.2(us)15.3(in)15(g)]TJ 0 -1.1174 TD -.0153 Tc [(a)-173.1(s)-15.3(ca)-15.3(n)-162.7(w)-15.3(in)-15.3(do)-15.3(w)-162.4(o)-15.3(f)-167.2(1)-15.3(,2)-15.3(00)-15.3(2)-15.3(,1)-15.3(00)-177.7(m)-15.3(/)4.2(z)-173.1(w)-15.3(it)-15.3(h)-161.6(a)-173.1(s)-15.3(p)0(r)-15.3(a)-1.3(y)-171.9(v)-15.3(ol)-15.3(ta)-15.3(ge)-173.1(o)-15.3(f)-161.5(4)-171.9(k)-15.3(V)]TJ 0 -1.1116 TD 0 Tc [(an)13.9(d)-329.4(3)0(5)-324.7(p)0(s)15.3(i)0(g)-324.9(o)0(f)-324.7(s)0(h)15.3(e)0(a)12.8(t)0(h)-324.9(g)0(a)19.7(s)-335(o)15.2(w,)-322.2(12)-152(L/)13.8(mi)13.7(n,)-321.3(33)15.1(5)]TJ /F8 1 Tf 18.6787 0 TD ()Tj /F3 1 Tf .3917 0 TD .3304 Tc [(Cd)330.4(r)345.5(y)330.4(i)345.4(n)330.4(g)5.7(g)330.4(a)344.3(s)]TJ -19.0704 -1.1116 TD 0 Tc [(o)15.2(w)-174.8(u)0(s)15.3(i)0(n)20.7(g)-173.9(a)-169.3(c)0(a)12.8(p)0(i)15(l)0(l)14.8(a)0(r)14(y)-168.1(vo)15.1(lt)14.8(ag)13.9(e)-175(o)0(f)]TJ /F8 1 Tf 12.5619 0 TD (-)Tj /F3 1 Tf .5414 0 TD [(15)15.1(0)-156.6(V)0(.)-166.7(S)0(e)14.1(l)0(e)13.8(c)0(t)-164.8(i)0(o)20.7(n)-173.9(mo)13.9(ni)15(to)20.7(ri)15(ng)]TJ -13.1033 -1.1174 TD -.0144 Tc [(w)-14.4(a)-1.4(s)-383.9(p)-14.4(er)-14.4(fo)-14.4(rm)-14.4(ed)-384.1(f)-14.4(o).7(r)-384.1(t)-14.4(he)]TJ /F8 1 Tf 9.4978 0 TD 0 Tc (-)Tj /F3 1 Tf .5414 0 TD [(5)-375.5(c)0(h)19.7(a)0(r)14(g)0(e)-366.2(s)0(t)15.1(a)0(t)13.8(e)0(,)-362.8(a)0(n)13.9(d)-369.7(ch)13.9(ro)15.1(ma)18.4(to)15(gr)15.1(am)12.7(s)]TJ -10.0392 -1.1116 TD [(we)13(re)-233.7(an)13.9(al)13.8(yz)13.9(ed)-233.7(us)15.3(in)15(g)-243(A)0(g)14.2(i)0(l)20.6(e)0(n)13.9(t)-243.1(Ch)14(em)12.7(St)15.1(at)19.5(io)15(n)-243(s)0(o)15.3(f)0(t)15(w)0(a)13(r)0(e)14(.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 62.022 489.5432 Tm [(SRB1)-338.2(mRNA)-334(knockdown)-333.3(in)-330.2(liver)-335.1(and)-335.7(other)-335.1(tissues)]TJ /F3 1 Tf 9.843 0 0 9.843 72 473.1022 Tm [(App)13.1(rox)14(im)13.7(ate)11.5(ly)-180.9(100)-153.1(mg)-182(of)-186.5(liv)13.7(er)14(,)-187.7(kid)13.8(ney)12.8(,)-187.7(hea)11.7(rt,)-178.5(je)13.8(jun)13.8(um,)-179.7(and)]TJ -1.0137 -1.1174 TD [(qua)12.8(dri)13.9(cep)11.7(s)-306.2(was)-298.9(pla)12.7(ced)-299.4(int)13.7(o)-306.4(1)0(.)12.7(5)-162.4(mL)-304.1(Epp)12.8(end)12.8(orf)-297(via)12.7(ls)-301.6(wit)12.8(h)-306.4(the)]TJ 0 -1.1116 TD [(add)12.8(iti)13.6(on)-411.1(of)-416.9(an)-412.3(equ)12.8(al)-412.4(amo)11.6(unt)-406.6(of)-416.9(cer)11.7(am)12.7(ic)-418.2(pul)13.8(ver)12.8(izi)18.3(ng)-416.9(bea)11.7(ds)]TJ T* [(fol)13.9(low)13(ed)-268.3(by)-272.9(the)-263.8(add)12.8(iti)13.6(on)-267.1(of)-272.9(1.)12.7(2)-162.4(m)0(L)-275.3(o)0(f)-267.1(Inv)14(itr)13.8(oge)12.8(n)-271.8(lys)14(is)-272.8(buf)14(fer)]TJ T* [(con)12.8(tai)12.6(nin)13.9(g)-145.1(1)0(%)-147.3(b)0(e)13.9(tam)11.5(erc)11.7(apt)12.7(oet)12.7(han)12.8(ol)14.9(.)-153.2(Sam)17.5(ple)12.7(s)-150.7(wer)12(e)-146.2(pul)13.8(ver)12.8(ize)11.5(d)]TJ 0 -1.1174 TD [(usi)14(ng)-284.4(a)-290.2(Pre)13(ce)12.8(lly)13.7(s)-288.9(2)0(4)-284.4(hig)13.8(h-t)13.9(hro)14(ugh)14(put)-279.9(tis)13.9(sue)-280.7(ho)15.1(mog)12.7(eni)12.7(zer)-282.1(for)]TJ 0 -1.1116 TD [(30)-157.7(s)-265.8(t)0(o)-267.3(uni)13.8(for)14(mi)13.7(ty)-267.3(\(Be)11.8(rti)19.5(n)-271.8(Cor)13(p,)-263.7(Ro)14(ckv)12.8(ill)13.6(e,)-264.9(MD\))12.2(,)-268.4(and)-257.9(300)]TJ /F9 1 Tf 23.131 0 TD (m)Tj /F3 1 Tf .5472 0 TD (L)Tj -23.6782 -1.1116 TD [(was)-333.4(tra)12.7(nsf)14.2(err)12.9(ed)-337.4(to)-330.6(a)-342.1(2.0)-155.4(mL)-332.9(dee)11.7(p)-340.9(96-)14(wel)11.8(l)-341(p)0(l)14.9(ate)-334.1(fol)13.9(low)13(ed)-337.4(by)]TJ 0 -1.1174 TD [(add)12.8(iti)13.6(on)-290.2(of)-290.2(300)]TJ /F9 1 Tf 6.3242 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-296(o)0(f)-290.2(70%)-286.6(eth)12.7(ano)18.6(l)-295(t)0(o)-290.3(eac)10.5(h.)-286.8(Pla)12.8(tes)-286.6(wer)12(e)-296(the)12.7(n)]TJ -6.8713 -1.1116 TD [(vor)14(tex)12.7(ed)-383.5(for)-377.6(2)-162.4(min)12.6(,)-389.3(and)-378.8(100)]TJ /F9 1 Tf 11.7383 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-388.2(o)0(f)-382.3(lys)14(ate)-380.1(was)-385.3(ad)13.9(ded)-384.6(to)-382.5(the)]TJ -12.2855 -1.1116 TD [(Pur)14.2(eLi)11.5(nk)-238.3(Pro)-239.3(96)-244.1(tot)13.7(al)-239.6(RNA)-242.2(Pur)14.2(ic)12.8(ati)12.6(on)-238.3(Fil)13.9(ter)-240.7(Pla)12.8(te.)-237.3(Sam)11.7(ple)12.7(s)]TJ 0 -1.1174 TD [(wer)12(e)-393.9(cov)12.8(ere)11.7(d)-392.8(wit)12.8(h)-392.8(Air)13(por)14(e)-393.9(tap)12.7(e)-393.9(she)13(ets)-390.3(and)-384.6(cen)11.7(tri)13.8(fug)14(ed)-389.3(for)]TJ 0 -1.1116 TD [(2)-162.4(min)-229.3(at)-233.9(3,)12.7(000)]TJ /F7 1 Tf 5.6388 0 TD (g)Tj /F3 1 Tf .4953 0 TD [(.)-239.6(The)-230.3(ow)-228.6(thr)13.9(oug)14(h)-237.2(was)-229.8(dis)14(car)11.7(de)13.9(d,)-234.9(and)-229.1(500)]TJ /F9 1 Tf 16.9969 0 TD (m)Tj /F3 1 Tf .5472 0 TD (L)Tj -23.6782 -1.1116 TD [(of)-238.3(was)12.1(h)-237.2(buf)14(fer)-234.8(I)-237.2(was)-235.5(add)12.8(ed)-233.8(to)-238.5(eac)10.5(h)-237.2(wel)11.8(l)-243.1(o)0(f)-232.6(the)-235(lt)13.9(er)-239.5(pl)15(ate)-236.1(and)]TJ T* [(cen)11.7(tri)13.8(fug)14(ed)-400.8(at)-395.2(3,0)11.6(00)]TJ /F7 1 Tf 8.2825 0 TD (g)Tj /F3 1 Tf .9043 0 TD [(fo)15.1(r)-404.2(2)-162.4(min)-396.3(wit)12.8(h)-404.3(the)-390.5(ow)-395.7(thr)13.9(oug)14(h)-404.3(dis)14(-)]TJ -9.1867 -1.1174 TD [(car)11.7(ded)12.8(,)-279.9(t)0(h)15(e)0(n)-279.8(D)0(N)13.3(ase)-276.1(I)-277.5(a)0(t)-274.2(4)0(0)-157.7(U)-278.4(per)-269.4(80)]TJ /F9 1 Tf 14.6239 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L/w)11.8(ell)-269.7(was)-270.1(add)12.8(ed)-274.1(wit)12.8(h)]TJ -15.1711 -1.1116 TD [(inc)12.7(uba)12.8(tio)13.7(n)-554(a)0(t)-550.7(roo)14(m)-555.3(tem)11.5(pe)13.9(rat)12.7(ure)-545.8(for)-550.4(15)-151.9(min)12.6(,)-556.4(fol)13.9(low)13(ed)-550.5(by)]TJ T* (500)Tj /F9 1 Tf 1.653 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-244.2(o)0(f)-244.1(w)0(a)13(s)0(h)-243.9(buf)14(fer)-234.8(I.)]TJ -1.1865 -1.1174 TD [(Pla)12.8(tes)-159.9(wer)12(e)-169.3(rec)11.7(ent)12.7(rif)13.9(uge)12.8(d)-168.1(for)-164.5(2)-162.4(m)0(i)13.7(n)-173.9(at)-164.8(3,0)11.6(00)]TJ /F7 1 Tf 16.9393 0 TD (g)Tj /F3 1 Tf .4953 0 TD [(,)-170.5(and)-165.7(750)]TJ /F9 1 Tf 3.6805 0 TD (m)Tj /F3 1 Tf .5472 0 TD .1751 Tc [(Lo)175.1(f)]TJ -22.676 -1.1116 TD 0 Tc [(was)12.1(h)-220(buf)14(fer)-211.7(II)-215.2(\(17)14(.5)-160(mL)-212(was)-212.5(buf)14(fer)-211.7(II)]TJ /F8 1 Tf 14.9061 0 TD (+)Tj /F3 1 Tf .5472 0 TD [(70)-157.7(mL)-217.7(of)-215.3(eth)12.7(ano)12.8(l\))-215.4(was)]TJ -15.4533 -1.1116 TD [(add)12.8(ed)-308.6(to)-313.4(ea)12.8(ch)-314.4(we)13(ll,)-305.4(sam)11.8(ple)12.7(s)-311.9(wer)12(e)-319(r)0(e)14(cen)11.7(tif)13.8(uge)12.8(d)-312.1(and)-309.7(an)-308.6(add)12.8(i-)]TJ 0 -1.1174 TD [(tio)13.7(nal)-338.7(750)]TJ /F9 1 Tf 4.2622 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-347.9(o)0(f)-342(was)12.1(h)-346.7(buf)14(fe)14(r)-346.6(I)0(I)-342(and)-338.5(cen)11.7(tri)13.8(fug)19.8(ati)12.6(on)-342(was)-339.2(per)12.8(-)]TJ -4.8094 -1.1116 TD [(for)14(med)-184.2(fol)13.9(low)13(ed)-187.7(by)-186.5(a)-192.3(lon)13.9(ger)-188.7(du)15.1(rat)12.7(ion)-187.7(of)-186.5(5)-162.4(min)-183.2(to)-186.6(dry)-181.8(the)-183.1(lt)13.9(er.)]TJ T* [(A)-278.4(n)0(e)13.9(w)-278.4(96-)14(wel)11.8(l)-271.9(pla)12.7(te)-268.4(was)-270.1(use)13(d,)-269.5(and)-263.6(pur)14(ie)12.9(d)-271.8(RNA)-271(wa)13(s)-277.4(elu)12.7(ted)]TJ 0 -1.1174 TD [(wit)12.8(h)-369.7(100)]TJ /F9 1 Tf 3.7899 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-370.9(o)0(f)-365(RNa)10.9(se-)13(fre)12.9(e)-370.9(H)]TJ 7.3823 0 0 6.5614 181.3606 208.4598 Tm (2)Tj 9.843 0 0 9.843 185.0456 210.0472 Tm [(O.)-362.5(Sam)11.8(ple)12.7(s)-369.5(wer)12(e)-370.9(qua)12.8(nti)13.7(tat)12.6(ed)]TJ -12.4986 -1.1116 TD [(usi)14(ng)-244.1(Rib)12.8(oGr)13.1(ee)12.8(n,)-246.4(pre)12.8(par)12.8(ed)-239.5(by)-244.1(55)]TJ /F9 1 Tf 13.3683 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-250(o)0(f)-238.3(Rib)12.8(oGr)13.1(een)]TJ /F8 1 Tf 6.543 0 TD (+)Tj /F3 1 Tf .5472 0 TD [(17.)17.4(5)-162.4(m)0(L)]TJ -21.0056 -1.1116 TD [(of)-180.7(TE)12.7(1X)-181.6(an)13.9(d)-185.4(170)]TJ /F9 1 Tf 6.9001 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-180.8(was)-172.2(add)12.8(ed)-176.2(to)-180.9(10)]TJ /F9 1 Tf 7.1939 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-180.8(o)0(f)-175(sam)11.8(ple)-171.6(int)13.7(o)-185.4(a)-180.8(cle)11.5(ar)]TJ -15.1883 -1.1116 TD [(bot)13.8(tom)-148.6(96-)14(wel)11.8(l)-156.7(pla)12.7(te)13.8(.)-158.9(A)-157.5(sta)12.9(nda)12.8(rd)-151.9(cur)12.8(ve)-153.1(was)-149.1(als)12.9(o)-156.6(pre)12.8(par)12.8(ed)-153.1(fro)14(m)]TJ 0 -1.1174 TD [(com)11.6(bin)13.8(ed)-239.5(sam)11.8(ple)-235(RNA)-236.5(fro)14(m)-244.2(1.5)11.7(6)-243(t)0(o)-244.2(2)0(0)15.1(0)-162.4(ng/)13.8(mL.)]TJ 1.0137 -1.1116 TD [(Plates)-296.8(were)-295.6(read)-300.4(using)-293.4(a)-296(uorescence)-299.8(excitation/emission)]TJ -1.0137 -1.1116 TD [(wavelength)-263.3(of)-261.4(500/525)-163.4(nm)-262.6(using)-258.9(a)-255.7(SpectraMax)-264.2(Gemini)-263.6(XPS)]TJ 0 -1.1174 TD [(plate)-486.1(reader)-488.1(with)-483.6(SoftMax)-487.8(Pro)-481.2(v5.4)-484.8(\()-81.7(Molecular)-486.8(Devices,)]TJ 0 -1.1116 TD [(Sunnyvale,)-459.1(CA\).)-457.9(RiboGreen)-457.7(data)-456.1(were)-456.8(used)-460.4(to)-451.6(normalize)]TJ T* [(RNA)-495.7(values,)-496.1(and)-494(corresponding)-494.6(samples)-494.8(were)-497.1(diluted)-493.1(to)]TJ 0 -1.1174 TD [(25)-169.2(ng/mL.)-299.5(A)-295.7(qPCR)-300.1(master-mix)-303.8(was)-298.9(prepared)-300.2(with)-299.3(the)-298.3(addi-)]TJ 0 -1.1116 TD [(tion)-269.6(of)-267.1(800)]TJ /F9 1 Tf 4.5962 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-267.2(o)0(f)-267.1(express)-268.8(superscript)-273.4(qPCR)-265.5(supermix,)-268(20)]TJ /F9 1 Tf 17.976 0 TD (m)Tj /F3 1 Tf .5529 0 TD (L)Tj -23.6782 -1.1116 TD [(of)-462.9(10)]TJ /F9 1 Tf 2.4652 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(M)-462.8(forward)-464.7(SRB1)-467.1(primer,)-461.8(20)]TJ /F9 1 Tf 12.3834 0 TD (m)Tj /F3 1 Tf .5529 0 TD .463 Tc [(Lo)463(f1)463(0)]TJ /F9 1 Tf 3.5422 0 TD 0 Tc (m)Tj /F3 1 Tf .5529 0 TD [(M)-462.8(reverse)]TJ -20.0495 -1.1174 TD [(SRB1)-242.5(primer,)-242.9(20)]TJ /F9 1 Tf 6.9635 0 TD (m)Tj /F3 1 Tf .5529 0 TD .2384 Tc [(Lo)238.4(f5)]TJ /F9 1 Tf 2.5919 0 TD 0 Tc (m)Tj /F3 1 Tf .5529 0 TD [(M)-243.9(probe,)-240.5(32)]TJ /F9 1 Tf 5.0628 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-244.2(o)0(f)-238.3(ROX)-242.2(reference)]TJ -16.2769 -1.1116 TD [(dye,)-169.2(160)]TJ /F9 1 Tf 3.5307 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-163.6(o)0(f)-169.2(express)-165.1(superscript)-169.8(mix)-165.9(for)-170.3(one)-165.7(step)-166.8(qPCR,)-165.3(and)]TJ 21.4203 67.9184 TD (388)Tj /F9 1 Tf 1.6703 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-313.3(o)0(f)-307.4(RNase)-9.5(-free)-313(H)]TJ 7.3823 0 0 6.5614 410.3999 723.5148 Tm (2)Tj 9.843 0 0 9.843 414.0849 725.1588 Tm [(O.)-310.7(Individual)-317.8(reactions)-312.9(were)-318.6(setup)]TJ -10.2638 -1.1174 TD [(into)-309.9(the)-304.1(96-well)-303.7(plate)-307.6(using)-304.9(2)]TJ /F9 1 Tf 12.1703 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-301.8(o)0(f)-307.4(sample)-303.8(RNA)-311.3(combined)]TJ -12.7232 -1.1116 TD [(with)-310.8(18)]TJ /F9 1 Tf 3.26 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-307.6(o)0(f)-307.4(master-mix)-309.6(per)-309.7(well.)-309.6(A)-307.2(standard)-310.5(cycling)-315.6(pro-)]TJ -3.8129 -1.1116 TD [(gram)-162.3(was)-160.7(used)-155.1(with)-161(an)-158.9(initial)-159.3(hold)-154.3(at)-159(50)]TJ /F8 1 Tf 15.3035 0 TD ()Tj /F3 1 Tf .3917 0 TD [(C)-157.6(for)-158.7(15)-169.2(min)-154.4(followed)]TJ -15.6952 -1.1116 TD [(by)-278.7(denaturation)-282(at)-274.2(95)]TJ /F8 1 Tf 8.582 0 TD ()Tj /F3 1 Tf .3917 0 TD [(C)-278.6(with)-276.2(a)-278.7(2-min)-271.8(hold,)-278.7(and)-275.2(40)-278.7(cycles)-275(of)]TJ -8.9736 -1.1174 TD (95)Tj /F8 1 Tf 1.0022 0 TD ()Tj /F3 1 Tf .3974 0 TD [(C)-267.1(for)-262.4(15)-169.2(s)-260.1(and)-269.4(60)]TJ /F8 1 Tf 6.8886 0 TD ()Tj /F3 1 Tf .3974 0 TD [(C)-267.1(for)-262.4(1)-168.1(min)-263.8(using)-264.6(a)-267.2(StepOnePlus)-268.5(Real-)]TJ -8.6856 -1.1116 TD [(Time)-313.4(PCR)-304.7(system)-314(and)-304(with)-310.8(v2.3)-306.2(software)-311.4(\(Applied)-310.6(Biosys-)]TJ T* [(tems,)-505.5(Carlsbad,)-510.8(CA\).)-503.9(Corresponding)-506(cycle)-504.5(threshold)-506.4(\(C)]TJ 7.3823 0 0 6.5614 546.803 646.8093 Tm (t)Tj 9.843 0 0 9.843 548.9006 648.4534 Tm (\))Tj -23.9604 -1.1174 TD [(value)-8(s)-185.2(normalized)-194.5(by)-186.5(RiboGreen)-192.8(were)-191.9(used)-189.7(to)-192.4(evaluate)-192.3(SRB1)]TJ 0 -1.1116 TD [(expression)-329.8(in)-324.9(liver,)-327.1(kidney,)-322.4(heart,)-328.1(lung,)-324.7(jejunum,)-324.8(and)-327(quad-)]TJ T* [(riceps)-8.8(.)-239.6(Percent)-241.5(SRB1)-242.5(RNA)-242.2(inhibition)-242.1(compared)-243.9(to)-244.2(the)-240.7(saline)]TJ 0 -1.1174 TD [(control)-256.8(was)-252.8(determined)-252.1(across)-256.2(all)-246.6(dose)-253(groups.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 313.0582 578.381 Tm [(Inhibitory)-336.5(effect)-335.1(liver)-335.1(exposure)-333.1(response)-333.1(PD)-335.8(model)]TJ /F3 1 Tf 9.843 0 0 9.843 323.0361 561.94 Tm [(Phoenix)-527.2(Build)-530.9(6.4.0.768)-523.8(WinNonlin)-531.8(was)-529.3(used)-523.7(for)-527.4(PD)]TJ -1.0137 -1.1116 TD [(modeling)-311(and)-309.7(simulation)-307.5(\(Certara,)-316.3(St.)-305.1(Louis,)-309.6(MO\).)-308(Data)-307.2(set)]TJ T* [(assembly)-426.8(was)-425.6(constructed)-430.3(using)-420.1(animal)-425.1(number,)-427.1(time)-421.8(\(h\),)]TJ 0 -1.1174 TD [(dose)-518(\(mg/kg\),)-513.5(liver)-513.7(concentration)-514.7(\()]TJ /F9 1 Tf 15.0098 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/g\),)-509(percent)-518.2(mRNA)]TJ -15.5627 -1.1116 TD [(inhibition)-507(compared)-508.8(to)-503.4(saline)-510.1(control)-504.4(\(%\),)-503.1(and)-505.6(knockout)]TJ T* [(status)-249.5(\(WT/WT,)-247.4(or)-238.3(HO/HO)-9.1(\).)-240.6(The)-241.8(data)-248.8(set)-240.6(was)-247.1(then)-247.6(imported)]TJ 0 -1.1174 TD [(into)-263.8(an)-262.5(inhibitory)-259.2(effect)-269.4(sigmoid)-256.7(maximum)-266.1(effect)-263.6(\(E)]TJ 7.3823 0 0 6.5614 521.0645 494.5888 Tm (max)Tj 9.843 0 0 9.843 533.8203 496.1763 Tm .2602 Tc [(\)P)260.2(D)]TJ -22.4283 -1.1116 TD 0 Tc [(model,)-253.4(whereby)-252.8(effect)-252.1(C)]TJ /F8 1 Tf 10.0852 0 TD (=)Tj /F3 1 Tf .72 0 TD .2493 Tc [(0i)249.3(sE)]TJ 7.3823 0 0 6.5614 441.8077 483.5905 Tm 0 Tc (max)Tj 9.843 0 0 9.843 457.0582 485.2345 Tm [(and)-252.1(effect)-252.1(at)-251.2(C)]TJ /F8 1 Tf 6.0477 0 TD (=)Tj /F3 1 Tf .72 0 TD (innity)Tj -21.3973 -1.1116 TD [(is)-284.4(E)]TJ 7.3823 0 0 6.5614 328.4786 472.6487 Tm (0)Tj 9.843 0 0 9.843 332.1637 474.2928 Tm [(,)-279.9(using)-281.9(the)-281.1(following)-281.9(equation:)]TJ /F7 1 Tf 4.1009 -3.0354 TD (E)Tj /F11 1 Tf .8006 0 TD ()Tj /F7 1 Tf .9388 0 TD (E)Tj /F3 1 Tf 6.8899 0 0 6.8899 395.6597 442.9416 Tm (0)Tj /F12 1 Tf 9.843 0 0 9.843 399.6282 458.2487 Tm ()Tj /F3 1 Tf .7315 -1.4054 TD (1)Tj /F11 1 Tf .6624 0 TD ()Tj ET 429.789 446.683 48.586 .39685 re f BT /F7 1 Tf 9.843 0 0 9.843 447.9306 451.1054 Tm (C)Tj /F3 1 Tf 6.8899 0 0 6.8899 454.7904 454.6771 Tm (Y)Tj /F7 1 Tf 9.843 0 0 9.843 429.7888 437.6692 Tm (C)Tj /F3 1 Tf 6.8899 0 0 6.8899 436.6487 440.5038 Tm (Y)Tj /F11 1 Tf 9.843 0 0 9.843 443.7353 437.6692 Tm ()Tj /F7 1 Tf .9331 0 TD (EC)Tj /F3 1 Tf 6.8899 0 0 6.8899 465.5621 436.1952 Tm (50)Tj 1.0697 .6254 TD (Y)Tj /F12 1 Tf 9.843 0 0 9.843 422.5889 458.2487 Tm 4.9386 Tc [()4938.6()]TJ /F3 1 Tf -11.1278 -4.2334 TD 0 Tc (whereby)Tj /F7 1 Tf 3.7381 0 TD (E)Tj /F8 1 Tf .7776 0 TD (=)Tj /F3 1 Tf .72 0 TD [(%)-290.1(saline)-285.5(inhibition)-288.1(in)-284.5(liver,)]TJ /F7 1 Tf 11.3927 0 TD (E)Tj /F3 1 Tf 7.3823 0 0 6.5614 482.74 414.9353 Tm (0)Tj /F8 1 Tf 9.843 0 0 9.843 488.0692 416.5794 Tm (=)Tj /F3 1 Tf .72 0 TD (lowest%saline)Tj -18.5002 -1.1174 TD .0184 Tc (inhibition,)Tj /F7 1 Tf 4.6423 0 TD 0 Tc (C)Tj /F8 1 Tf .8524 0 TD (=)Tj /F3 1 Tf .7372 0 TD .0185 Tc [(liver)-287.8(concentration,)]TJ /F9 1 Tf 8.4783 0 TD 0 Tc (g)Tj /F8 1 Tf .6854 0 TD (=)Tj /F3 1 Tf .7372 0 TD .0187 Tc [(hill)-282(coefcient,)-284.2(a)-.8(nd)]TJ -16.1329 -1.1116 TD .0196 Tc (EC)Tj 7.3823 0 0 6.5614 326.0409 392.9952 Tm .0299 Tc (50)Tj /F8 1 Tf 9.843 0 0 9.843 335.4519 394.6393 Tm 0 Tc (=)Tj /F3 1 Tf .7372 0 TD .0186 Tc [(concentration)-212.9(r).3(equired)-207.1(f).3(or)-212.8(50%)-213.9(inhibition.)-209.4(Uniform)]TJ -3.0123 -1.1116 TD [(weighting)-460.7(u).1(sing)-460.7(initial)-460.8(p).1(arameter)-5.6(s/bounds)-454.7(with)-460.6(Nelder)]TJ 0 -1.1174 TD 0 Tc [(Me)13(ad)-268.3(mi)19.5(ni)14.9(mi)19.5(za)18.5(ti)20.6(on)-272.9(wa)18.8(s)-283.1(u)0(s)21(e)0(d)19.7(,)-285.6(an)19.7(d)-283.3(E)0(C)]TJ 7.3823 0 0 6.5614 462.5573 371.055 Tm -.0162 Tc (50)Tj 9.843 0 0 9.843 472.6487 372.6991 Tm 0 Tc [(va)19.7(lu)20.7(es)-273.9(fo)20.9(r)-283.3(b)0(o)20.8(t)0(h)-273(W)0(T)17.4(/)]TJ -16.2136 -1.1116 TD [(WT)-264.8(an)19.7(d)-271.8(H)0(O)19.1(/)0(H)19.8(O)-272.7(co)19.7(ho)20.8(rt)20.7(s)-271.6(w)0(e)18.8(r)0(e)-262.5(c)0(o)19.7(m)0(p)19.6(a)0(r)19.7(e)0(d)19.7(.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 313.0582 334.5448 Tm (Immunohistochemistry)Tj /F3 1 Tf 9.843 0 0 9.843 323.0361 318.1038 Tm [(Fo)26.8(r)16.2(m)0(a)24.2(l)16.1(in)-175.1()16.3(x)0(e)25.4(d)-185.4(pa)25.4(r)16.2(a)0(f)25.5()0(n)-174.8(s)16.4(e)15(c)0(t)25.3(i)0(o)26.5(n)16.2(s)-191(o)16.2(f)-185.4(m)15(ur)26.6(i)16.1(n)0(e)-176.1(l)16.1(iv)26.5(e)15(r)-185.4(we)24.6(re)-176.1(c)15(u)16.2(t)-185.5(a)0(n)25.4(d)]TJ -1.0137 -1.1116 TD [(se)25.6(ct)25.3(i)16.1(o)0(n)26.6(e)0(d)-147.4(a)15(t)-156.7(4)]TJ /F9 1 Tf 5.3623 0 TD (m)Tj /F3 1 Tf .5414 0 TD [(m)15(,)-153.2(an)25.4(d)-156.6(s)16.4(li)26.3(de)25.4(s)-156.4(w)15.3(er)25.5(e)-157.8(d)16.2(ri)26.5(ed)-147.4(o)16.2(v)16.2(e)0(r)25.5(n)0(i)26.5(g)16.2(ht)-146.3(i)16.1(n)-156.6(a)15(n)-156.6(ov)26.6(e)15(n)-156.6(se)25.6(t)]TJ -5.9037 -1.1116 TD [(to)-491.9(5)16.2(0)]TJ /F8 1 Tf 2.2405 0 TD ()Tj /F3 1 Tf .3859 0 TD [(C)15.2(.)-504.5(T)15(h)16.2(e)-503.3(s)16.4(li)26.3(de)25.4(s)-502(w)15.3(er)25.5(e)-503.4(t)16(he)25.4(n)-502.2(d)16.2(ep)25.4(a)15(r)0(a)25.5(f)0()26.8(n)16.2(iz)25.3(e)15(d)-502.2(wi)25.6(t)16.1(h)-502.2(xy)26.6(l)16.1(e)0(n)25.4(e)]TJ -2.6264 -1.1174 TD [(tr)26.5(ea)24.3(t)16.1(m)0(e)24.2(n)16.2(t)-513.8(f)16.2(or)-497.5(1)16.2(0)-156.6(m)15(i)16.1(n)-513.7(f)16.2(o)16.2(l)0(l)26.3(o)0(w)25.7(e)15(d)-513.7(b)16.2(y)-507.9(1)0(0)26.6(0)0(%)-498.6(e)15(th)26.5(y)16.2(l)-513.8(a)15(l)16.1(co)25.4(ho)26.6(l)-508.1(f)0(o)26.6(r)]TJ 0 -1.1116 TD [(10)-140.4(m)15(i)0(n)26.5(,)-233.8(95)26.6(%)-232.5(e)0(t)25.3(h)16.2(yl)-221.2(a)15(l)0(c)25.3(o)0(h)26.6(o)16.2(l)-237.4(f)16.2(or)-221(6)-150.8(m)0(i)25.2(n)16.2(,)-233.8(a)0(n)25.4(d)-231.5(ri)26.5(ns)26.8(ed)-222.2(w)15.3(i)0(t)26.3(h)-231.5(wa)24.6(te)25.3(r)-231.5(f)0(o)26.6(r)]TJ T* [(2)-156.6(m)15(i)16(n)0(.)-171.6(E)15(n)16.2(d)0(o)26.6(g)0(e)25.4(n)16.2(ou)26.6(s)-185.2(p)16.2(e)15(r)0(o)26.6(x)16.2(id)26.5(as)25.6(e)-180.8(w)0(a)24.6(s)-179.5(qu)26.6(en)25.4(c)15(h)0(e)25.4(d)-179.6(pl)26.5(ac)24.3(i)16.1(n)0(g)-169.2(t)16.1(he)-170.4(sl)26.7(i)16(d)0(e)25.4(s)]TJ T* [(in)-290.3(3)16.2(%)-301.7(hy)26.6(dr)26.6(o)16.2(g)0(e)25.4(n)-300.6(pe)25.4(r)16.2(o)0(x)26.6(i)0(d)26.5(e)-301.8(f)16.2(o)0(r)-290.2(1)16.2(5)-156.6(m)15(i)16(n)0(.)-286.8(S)0(l)26.6(i)0(d)26.5(e)15(s)-306.2(w)15.3(e)15(r)0(e)-291.3(t)16.1(he)25.4(n)-300.6(r)16.2(in)26.5(se)25.6(d)]TJ 0 -1.1174 TD [(wi)25.6(th)-134.8(1)]TJ /F8 1 Tf 2.373 0 TD ()Tj /F3 1 Tf .7027 0 TD -.0158 Tc [(TBS)-160.7(f)-15.8(o)10.8(r)-160.9(5)-172.4(m)-.8(in)-166.6(and)-166.6(t).3(re)-15.8(a)8.5(t)-15.8(e)9.5(d)-160.9(wi)-15.8(t)10.5(h)-166.6(Pro)-15.8(t)10.7(e)-15.8(i)9.5(na)-15.8(s)9.8(e)-162.1(K)-167.5(for)-166.6(5)-166.6(m)-.8(i)-15.8(n)-150.6(at)]TJ -3.0757 -1.1116 TD 0 Tc [(ro)26.6(om)-435.4(t)16.1(e)0(m)24.2(p)16.2(er)25.5(a)15(t)0(u)26.5(r)0(e)25.5(.)-446.9(S)16.3(l)0(i)26.3(d)0(e)25.4(s)-444.4(we)24.6(r)16.2(e)-451.5(r)16.2(i)0(n)26.5(s)16.4(ed)-435.3(a)15(g)0(a)25.4(i)0(n)-434.3(w)15.3(it)26.3(h)-444.6(T)0(B)24.4(S)-444.4(an)25.4(d)]TJ T* [(bl)26.5(oc)25.4(k)16.2(e)0(d)-435.3(w)15.3(i)16.1(t)0(h)-434.3(p)16.2(ro)26.6(t)16(e)0(i)25.3(n)-444.6(bl)26.5(o)16.2(c)0(k)25.4(i)0(n)26.5(g)-444.6(s)16.4(o)0(l)26.5(u)0(t)26.5(i)16.1(on)-434.2(f)16.2(o)0(r)-428.4(2)0(0)-140.4(m)15(in)-434.3(a)15(t)-444.7(ro)26.6(o)16.2(m)]TJ 0 -1.1174 TD [(te)25.3(m)15(p)0(e)25.4(r)0(a)25.5(t)16(ur)26.6(e.)-224.6(Sl)26.6(i)16.1(d)0(e)25.4(s)-237(we)24.6(r)16.2(e)-238.4(re)25.5(r)16.2(i)0(n)26.5(s)0(e)25.6(d)-237.2(w)15.3(i)0(t)26.3(h)-237.2(T)15(B)0(S)25.7(,)-239.6(a)15(n)16.2(d)-237.2(p)0(r)26.6(i)0(m)25.2(a)15(ry)-226.8(a)15(n)16.2(ti)26.3(-)]TJ 0 -1.1116 TD [(bo)26.6(dy)-267.1(\()16.2(R)0(a)24.4(b)16.2(bi)26.5(t)-283.5(a)15(n)16.2(t)0(i)26.3(-)0(A)25.8(S)16.3(O)-284.2(A)15.3(n)16.2(t)0(i)26.3(b)0(o)26.6(d)16.2(y\))-267.1(wa)24.6(s)-277.4(a)0(d)25.4(d)16.2(ed)-268.3(a)15(t)-283.5(1)16.2(:)0(1)26.5(0)16.2(,)13.9(0)0(0)26.6(0)-277.6(an)25.4(d)]TJ T* [(in)26.5(cu)25.4(b)16.2(a)0(t)25.3(e)0(d)-199.2(o)16.2(ve)25.4(rn)26.6(i)16(g)0(h)26.6(t)-214.3(a)15(t)-208.6(4)]TJ /F8 1 Tf 9.3653 0 TD ()Tj /F3 1 Tf .3801 0 TD [(C)15.2(.)-210.8(Sl)26.6(id)26.5(e)15(s)-214(w)15.3(e)0(r)25.5(e)-209.6(re)25.5(ri)26.5(n)16.2(s)0(e)25.6(d)-214.2(w)15.3(i)0(t)26.3(h)-208.4(TB)24.4(S)-208.3(a)0(n)25.4(d)]TJ -9.7454 -1.1174 TD [(go)26.6(at)-130.2(a)15(n)0(t)26.5(i)16.1(-r)26.7(ab)25.4(b)16.2(i)0(t)-129.2(s)0(e)25.6(c)15(on)26.6(d)16.2(a)0(r)25.5(y)-139.3(an)25.4(ti)26.3(b)16.2(o)0(d)26.6(y)-139.3(wa)24.6(s)-139.1(a)0(d)25.4(d)0(e)25.4(d)-139.3(a)15(t)-145.2(1)16.2(:)16(20)26.6(0)-139.3(d)0(i)26.5(l)0(u)26.5(t)16(io)26.5(n,)]TJ 0 -1.1116 TD [(an)25.4(d)-156.6(i)16(nc)25.4(u)16.2(b)0(a)25.4(t)0(e)25.3(d)-150.8(fo)26.6(r)-156.6(3)16.2(0)-156.6(m)15(i)16.1(n)-156.6(a)15(t)-156.7(r)16.2(o)0(o)26.6(m)-152.1(te)25.3(m)15(p)0(e)25.4(r)0(a)25.5(t)16(ur)26.6(e)-157.8(\()16.2(RT)24.4(\))16.2(.)-153.2(Sl)26.6(id)26.5(e)15(s)-156.4(w)15.3(e)0(r)25.5(e)]TJ T* [(re)25.5(ri)26.5(ns)26.8(e)15(d)-179.6(w)15.3(i)0(t)26.3(h)-179.6(T)15(B)15.2(S,)-165.6(a)15(n)0(d)-163.5(D)15.3(AB)-165.4(Ch)25.6(r)16.2(o)0(m)25.4(a)15(ge)25.4(n)-179.6(w)15.3(a)15(s)-179.5(a)15(p)0(p)26.6(l)0(i)26.3(e)15(d)-179.6(f)16.2(or)-163.4(5)-156.6(m)15(i)16.1(n)]TJ 0 -1.1174 TD [(at)-297.2(R)15.2(T)15(,)-302.9(r)0(i)26.5(n)0(s)26.8(e)0(d)-291.3(i)0(n)-290.3(H)]TJ 7.3823 0 0 6.5614 384.8314 141.1653 Tm (2)Tj 9.843 0 0 9.843 388.403 142.7527 Tm [(O)-301.5(f)0(o)26.6(r)-306.3(3)-150.8(m)15(in)26.5(,)-302.9(a)0(n)25.4(d)-306.4(c)15(o)0(u)26.6(n)16.2(te)25.3(rs)26.8(ta)25.3(i)16.1(n)0(e)25.4(d)-306.4(b)16.2(y)-306.4(h)16.2(e)0(m)24.2(a)15(-)]TJ -7.6546 -1.1116 TD [(to)26.5(xy)26.6(l)16.1(i)0(n)-226.9(i)16(nc)25.4(ub)26.6(a)15(t)0(i)26.3(o)0(n)-226.8(f)16.2(o)16.2(r)-243(3)16.2(0)-150.8(s,)-229(f)16.2(o)16.2(l)0(l)26.3(o)0(w)25.7(e)15(d)-237.2(b)0(y)-226.8(a)-238.4(H)]TJ 7.3823 0 0 6.5614 480.8125 130.1669 Tm (2)Tj 9.843 0 0 9.843 484.3841 131.811 Tm [(O)-238.1(r)0(i)26.5(n)0(s)26.8(e)-238.4(fo)26.6(r)-237.2(1)-156.6(m)15(i)16(n,)]TJ -17.4058 -1.1116 TD [(ac)24.3(id)-134.8(a)15(l)16.1(co)25.4(ho)26.6(l)-145.2(r)0(i)26.5(n)16.2(se)-135.6(f)16.2(o)0(r)-134.6(1)-150.8(s,)-131(H)]TJ 7.3823 0 0 6.5614 413.9715 119.2252 Tm (2)Tj 9.843 0 0 9.843 417.5432 120.8692 Tm [(O)-146(r)16.2(i)16.1(n)0(s)26.8(e)-146.3(fo)26.6(r)-145.1(3)-156.6(m)15(i)16.1(n,)-131.2(95)26.6(%)-146.1(e)0(t)25.3(h)16.2(yl)-134.8(a)15(l)0(c)25.3(o)16.2(ho)26.6(l)]TJ -10.6151 -1.1116 TD [(fo)26.6(r)-237.2(2)-156.6(m)15(i)16.1(n,)-223.4(1)16.2(0)0(0)26.6(%)-238.3(e)15(t)0(h)26.5(y)16.2(l)-237.4(a)0(l)25.3(c)15(oh)26.6(o)16.2(l)-237.4(fo)26.6(r)-237.2(3)-150.8(mi)25.2(n)16.2(,)-239.6(a)15(n)16.2(d)-237.2(x)0(y)26.6(l)16(en)25.4(e)-238.4(f)16.2(or)-226.8(2)-150.8(m)15(in)26.5(.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 313.0582 84.0189 Tm [(To)15.2(ta)23.7(l)-199.3(p)0(l)17.6(a)0(s)21.4(m)0(a)-189.4(p)0(r)18.8(o)14.6(te)17.3(in)-191.1(b)14.6(i)0(n)17.6(d)0(i)17.6(n)0(g)-185.9(a)0(n)22.8(d)-200.4(pr)18.8(ot)23.7(ei)17.6(n)-200.4(b)14.6(in)17.6(di)17.6(ng)-185.9(pr)18.8(o)21.4(li)18.7(ng)]TJ /F3 1 Tf 9.843 0 0 9.843 323.0361 67.5779 Tm [(An)-723(ultraltration)-721(method)-723.3(with)-725.5(a)-716.5(nuclease-dependent)]TJ -1.0137 -1.1174 TD [(hybrid)-6.7(ization)-471.2(ELISA)-469.4(was)-471.7(used)-466.1(to)-468.9(determine)-475.6(total)-467.8(protein)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (226)Tj 46.1699 0 TD [(SHEMESH)-334(ET)-338.7(AL.)]TJ ET endstream endobj 93 0 obj <>stream LDCNMC+AdvP4C4E46 wrOC18C19AdvP4C4E46 kSmPfHH5B9"ݷ}}||"^9 tbgmx1 web}gH5g9<"88aa^9{+;PWB> ( ||MO=B3^s587 4,# endstream endobj 96 0 obj <>stream hbd`ab`ddqquvL) 0q6q57+iW <~OI102,b񟁕)bW|j+_,:qҲ+7s,\9  z}~3u5H5,l_Z%bzݴߓuKO_>{|9S8~Ne{Vy~~m+kmfZk~a./=S;V]1~r@?5T,~BfPwWZKKwOm|JA.0 W endstream endobj 98 0 obj <>stream hT=o w~ǫ:2G M{R~v'`rH .x>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 59.7543 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(binding)-451.5(differences)-454.3(between)-455.7(sample)-453.6(types.)-447.8(The)-449.2(degree)-453.6(of)]TJ 0 -1.1174 TD [(plasma)-205.9(protein)-204.9(binding)-198(differences)-206.7(was)-201(evaluated)-210.7(using)-201.3(ION-)]TJ 0 -1.1116 TD [(353382)-409.8(at)-400.9(both)-407.7(5)-404.3(and)-407.6(150)]TJ /F9 1 Tf 11.1508 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/mL)-404.4(in)-405.5(WT/WT)-410(and)-407.6(HO/HO)]TJ -11.7037 -1.1116 TD [(fresh)-472.9(plasma.)-468.6(Nanosep)-477.3(\(30K\))-467.1(lters)-474.2(were)-468.3(pretreated)-476.6(with)]TJ T* (300)Tj /F9 1 Tf 1.6703 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-180.8(o)0(f)-186.5(0.5%)-186.3(Tween-80)-186(and)-188.8(incubated)-186.5(at)-187.8(room)-184.1(temperature)]TJ -2.2232 -1.1174 TD [(for)-291.2(15)-169.2(min)-292.6(followed)-293.3(by)-284.4(centrifugat)-10.2(ion)-285.7(at)-291.5(12,000)]TJ /F7 1 Tf 19.3181 0 TD (g)Tj /F3 1 Tf .7891 0 TD [(for)-291.2(10)-169.2(min)]TJ -20.1071 -1.1116 TD [(to)-370.9(minimize)-371.1(nonspecic)-371.4(binding.)-374.3(Retained)-370.7(volume)-372(was)-368(re-)]TJ T* [(moved)-295.9(by)-290.2(rinsing)-295.7(the)-292.6(membrane)-291.2(twice)-296.9(with)-293.5(300)]TJ /F9 1 Tf 19.6464 0 TD (m)Tj /F3 1 Tf .5529 0 TD .2903 Tc [(Lo)290.3(f)-5.6(H)]TJ 7.3823 0 0 6.5614 285.6188 646.8093 Tm 0 Tc (2)Tj 9.843 0 0 9.843 289.3605 648.4534 Tm (O,)Tj -23.3268 -1.1174 TD [(followed)-293.3(by)-284.4(the)-286.8(addition)-292.6(of)-284.4(300)]TJ /F9 1 Tf 13.0227 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-284.5(o)0(f)-284.4(a)-290.2(300)]TJ /F9 1 Tf 4.4177 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/mL)-289.2(aqueous)]TJ -18.5463 -1.1116 TD [(solution)-383.4(of)-376.5(ION-420476)-375.6(as)-383.3(a)-376.6(separate)-382(ASO)-379.3(with)-379.9(no)-376.6(cross-)]TJ T* [(reactivity)-458.5(to)-457.3(ION-353382)-456.2(to)-457.3(further)-458.2(minimize)-457.5(nonspecic)]TJ 0 -1.1174 TD [(binding.)-541.3(Filters)-533(were)-543.2(incubated)-537.8(at)-533.4(room)-535.5(temperatur)-10.2(e)-532.2(for)]TJ 0 -1.1116 TD [(10)-169.2(min)-281.1(and)-280.9(centrifuged)-286.5(at)-280(12,000)]TJ /F7 1 Tf 13.351 0 TD (g)Tj /F3 1 Tf .7833 0 TD [(for)-279.7(10)-169.2(min.)]TJ -13.1206 -1.1116 TD [(Recovery)-381.9(testing)-377.7(was)-379.5(performed)-376.2(to)-376.7(correct)-379.9(for)-377.6(any)-378.8(non-)]TJ -1.0137 -1.1116 TD [(specic)-350.8(binding)-342(and)-344.3(evaluated)-343.1(at)-343.3(250)-170.3(ng/mL,)-339.8(and)-344.3(three)-347.7(ali-)]TJ 0 -1.1174 TD [(quots)-546.9(of)-549.3(300)]TJ /F9 1 Tf 5.7597 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-549.5(o)0(f)-549.3(ION-353382)-548.4(were)-549(placed)-551.6(into)-546.1(three)]TJ -6.3126 -1.1116 TD [(pretreated)-384.5(lters)-376.3(and)-378.8(centrifuged)-378.7(at)-377.9(12,000)]TJ /F7 1 Tf 17.6881 0 TD (g)Tj /F3 1 Tf .8755 0 TD [(for)-377.6(7)-162.4(min.)-376.7(Ul-)]TJ -18.5635 -1.1116 TD [(traltrate)-245.2(\(ltered\))-236.9(samp)-12.4(l)-7(e)-13.8(s)-248.6(w)-7.7(e)-13.8(r)-6.8(e)-249.9(c)-8(o)-12.6(l)-7(l)-12.7(e)-8(c)-13.8(t)-12.7(e)-8(d)-248.8(i)-7(n)-248.8(a)-8(d)-12.6(d)-6.9(i)-12.7(t)-7(i)-12.7(o)-12.6(n)-243(t)-12.7(o)-243(t)-12.7(h)-6.9(e)]TJ 0 -1.1174 TD .0129 Tc [(ini)5.9(t).2(i)5.9(a)-.9(l)-333.9(s).5(a)4.9(m)-.9(p)6(l).2(es)-333.6(an)6(d)-339.5(a)4.9(ss)6.2(aye)4.9(d)-333.8(by)-333.8(EC)5(L-E)4.9(L)4.9(I).3(SA)-334.6(to)-333.8(ob)6(ta)4.9(in)-333.8(pe)4.9(r-)]TJ 0 -1.1116 TD .0117 Tc [(cent)-415.7(reco)4.8(very.)-412.2(Two)-415.6(c)-2.1(o)4.8(n)-.9(cen)4.8(t)-1(ra)]TJ 12.6829 0 TD .0123 Tc [(ti)5.3(ons)5.6(,)-417.3(i)5.3(nclud)5.4(i)-.4(n)5.4(g)-415(bo)5.4(th)-415(5)-415(a)4.3(nd)]TJ -12.6829 -1.1116 TD .0126 Tc (150)Tj /F9 1 Tf 1.6991 0 TD 0 Tc (m)Tj /F3 1 Tf .5645 0 TD .0119 Tc [(g)5(/)-.8(mL)-485.7(of)-484.5(ION-)5.1(35)5(338)5(2,)-481.1(were)-485.7(pr)5.1(ep)5(ared)-484.5(in)-484.5(1)5(.)-3(2)-162(m)3.8(L)-485.7(o)-.7(f)]TJ -2.2636 -1.1174 TD .0121 Tc [(who)5.2(l)-.6(e)-278.1(p)5.2(lasma)-278.1(fro)5.2(m)-278.2(W)3(T/)5.1(WT)-278.2(and)-277(H)4.4(O/)5.1(HO)-277.8(mice.)-273.6(S)-.3(pi)5.1(ked)-277(o)-.5(l)5.1(i)-.6(-)]TJ 0 -1.1116 TD [(gon)5.1(ucleoti)5(d)-.6(e)-168.8(d)-.6(id)-167.6(no)5.1(t)-173.5(e)-1.8(x)5.1(c)-1.8(eed)-173.4(1)5.1(.5%)-174.5(o)5.1(f)-173.4(t)-.7(h)5.1(e)-174.6(p)5.1(l)-.7(as)5.3(ma)-168.8(vol)5(ume,)-170(and)]TJ T* .011 Tc [(plasma)-336.8(pH)-336.5(was)-335.5(n)4.1(ear)-335.6(p)-1.6(h)4.1(y)-1.6(si)4(ol)4(ogi)4(cal)-335.8(l)-1.7(evels)-335.5(b)-1.6(etween)-335.7(7.3)-335.7(a)3(nd)]TJ 0 -1.1174 TD .013 Tc [(7.5.)-203.5(Sa)5(mp)6.1(les)-206.8(w)5.3(er)6.2(e)-208.1(i).3(n)6.1(c)-.8(ub)6.1(at)6(ed)-207(a)5(t)-207.1(37)]TJ /F8 1 Tf 13.8118 0 TD 0 Tc ()Tj /F3 1 Tf .4089 0 TD .0128 Tc [(C)-208.2(f)6(or)-207.1(30)-161.1(mi)5.8(n)-207.2(f).2(o)5.9(r)-207.1(bin)5.9(d).2(i)5.8(ng,)]TJ -14.2207 -1.1116 TD [(an)5.8(d)-310.9(t)5.7(hr)5.9(ee)-306.3(aliq)5.8(uo)5.8(ts)-305(o)12.7(f)-277.5(3)12.7(0)33.5(0)]TJ /F9 1 Tf 10.4827 0 TD 0 Tc (m)Tj /F3 1 Tf .5414 0 TD [(L)-301.8(w)0(e)18.8(r)0(e)-285.6(p)0(l)20.7(a)0(c)18.5(e)0(d)-291.3(i)0(n)-290.3(t)0(h)20.7(r)0(e)19.7(e)-296(pr)15.1(et)19.5(re)19.7(at)19.5(ed)]TJ -11.0241 -1.1116 TD [(l)15.1(te)19.6(rs)-330.3(an)19.7(d)-340.9(c)0(e)18.5(n)0(t)20.7(r)0(i)20.7(f)0(u)20.9(g)0(e)19.7(d)-340.9(at)-331.8(12)20.8(,0)18.5(00)]TJ /F7 1 Tf 12.9017 0 TD (g)Tj /F3 1 Tf .8409 0 TD [(fo)20.9(r)-340.9(7)-156.6(mi)19.5(n)-340.9(f)0(o)20.9(r)-340.9(co)19.7(ll)20.6(ec)18.5(ti)20.6(on)-330.5(of)]TJ /F9 1 Tf -13.7427 -1.1116 TD (*)Tj /F3 1 Tf .9907 0 TD [(20)20.8(%)-169.2(o)0(f)-157.7(i)0(n)20.7(i)0(t)20.6(i)0(a)19.5(l)-168.3(pl)20.7(as)19.9(ma)-160.1(vo)20.8(lu)20.7(me)]TJ /F9 1 Tf 11.5194 0 TD (*)Tj /F3 1 Tf .9849 0 TD (60)Tj /F9 1 Tf 1.1462 0 TD (m)Tj /F3 1 Tf .5472 0 TD -.0204 Tc [(L)-184(o)-20.4(f)-178.1()-20.4(lt)-20.4(ra)-20.4(te)-20.4(.)-181.6(A)-20.4(li)-20.4(qu)-20.4(ot)-20.4(s)-178(o)-20.4(f)]TJ -15.1883 -1.1174 TD 0 Tc [(ul)14.9(tr)20.7(a)19.8(lt)20.6(ra)19.7(te)19.5(s)-167.9(a)0(n)19.7(d)-168.1(in)20.7(it)20.6(ia)19.6(l)-168.3(p)0(l)20.7(a)0(s)19.9(m)0(a)-160.1(w)0(e)18.8(r)0(e)-153.1(a)0(s)14.1(s)0(a)19.9(y)0(e)19.7(d)-162.4(by)-157.7(EC)18.6(L-)19.7(EL)18.5(IS)21(A)-169(t)0(o)]TJ 0 -1.1116 TD [(qu)15.1(an)19.7(ti)20.6(ta)19.6(te)19.5(%)-376.5(b)0(o)20.8(u)0(n)20.8(d)-375.5(an)19.7(d)-375.5(u)0(n)20.8(b)0(o)20.8(u)0(n)20.8(d)-375.5(AS)20.1(O)-376.3(i)0(n)-365.2(s)0(a)19.9(m)0(p)19.6(l)0(e)19.6(s)0(.)-367.2(F)0(o)21(r)-375.4(to)20.7(ta)19.6(l)]TJ T* [(pl)14.9(as)19.9(ma)-263.8(pr)20.9(ot)20.7(ei)19.6(n)-271.8(b)0(i)20.7(n)0(d)20.8(i)0(n)20.7(g)0(,)-263.7(E)0(C)18.6(L)0(-)19.7(E)0(L)18.5(I)0(S)21(A)-272.7(wa)18.8(s)-271.6(p)0(e)19.7(r)0(f)15.1(o)0(r)20.9(m)0(e)18.4(d)-271.8(wi)19.8(th)-261.5(th)20.7(e)]TJ 0 -1.1174 TD [(sa)14.1(m)15(e)-261.4(me)18.4(th)20.7(od)-249.9(as)-256.6(de)19.7(ta)19.6(il)20.6(ed)-251(fo)20.9(r)-260.2(t)0(i)20.6(s)0(s)15.5(u)0(e)-251(e)0(x)19.7(p)0(o)20.8(s)0(u)21(r)0(e)-251(k)0(i)20.7(n)0(e)19.7(t)0(i)20.6(c)0(s)14.1(.)]TJ 1.0137 -1.1116 TD [(Protein)-250.8(binding)-249.9(proling)-250.8(was)-247.1(performed)-249.5(by)-249.9(size)-248.6(exclu)-8(sion)]TJ -1.0137 -1.1116 TD [(chromatogr)-8.9(aphy)-287.8(\(SEC\))-284(using)-287.7(ION-407988)-294.9(\(alexa-488)-291(uor-)]TJ 0 -1.1174 TD [(escently)-404(labeled)-403.1(version)-400.4(of)-399.6(ION-3553382\))-400.8(to)-399.7(interact)-404.3(with)]TJ 0 -1.1116 TD [(proteins)-298(present)-292.2(in)-290.3(nontreated)-297(WT/WT)-294.8(and)-292.4(HO/HO)-297.1(plasma.)]TJ T* [(The)-397.3(high-performance)-397.9(liquid)-387.1(chromatogr)-8.9(aphy)-391.5(\(HPLC\))-389.6(and)]TJ T* [(detector)-479.1(components)-475.3(included)-472.2(a)-474.6(G1332A)-469.1(1100)-470.9(series)-475.2(de-)]TJ 0 -1.1174 TD [(gasser,)-230.8(G1311A)-221.5(1000)-223.3(series)-227.5(quaternary)-227.7(pump,)-222.2(G1367A)-227.2(1100)]TJ 0 -1.1116 TD [(series)-480.9(autosampler,)-475.3(G1321A)-474.9(1200)-476.7(series)-475.2(uorescence)-478.3(de-)]TJ T* [(tector,)-323.6(G1315A)-319.4(1100)-321.2(series)-325.4(diode)-317.8(array,)-322.2(and)-321.2(a)-319(G1316)-323.2(1100)]TJ 0 -1.1174 TD [(se)14.1(ri)20.7(es)-291.2(co)19.7(lu)20.7(mn)-291.4(co)19.7(mp)19.6(ar)14(tm)25.2(en)13.9(t,)-286.9(al)19.5(l)-306.5(a)0(c)18.5(q)0(u)20.8(i)0(r)20.7(e)0(d)-291.3(f)0(r)20.9(o)0(m)-291.4(A)0(g)14.2(i)0(l)20.6(e)0(n)19.7(t)-300.7(Te)18.5(ch)19.7(-)]TJ 0 -1.1116 TD [(no)15.1(lo)20.7(gi)20.7(es)-469.7(\(W)18.6(il)20.6(mi)19.5(ng)20.8(to)15(n,)-465.3(DE)18.8(\).)-471(Ba)18.6(ck)19.7(gr)15.1(ou)20.8(nd)-468.7(en)19.7(do)20.8(ge)19.7(no)20.8(us)-474.3(u)21(o-)]TJ T* [(re)14(sc)19.9(en)19.7(ce)-384.7(wa)13(s)-392.6(o)0(b)20.8(t)0(a)13.8(i)0(n)20.7(e)0(d)-383.5(b)0(y)-388.1(i)0(n)20.7(c)0(u)19.7(b)0(a)13.9(t)0(i)20.6(n)0(g)-382.3(5)0(0)]TJ /F9 1 Tf 16.5764 0 TD (m)Tj /F3 1 Tf .5472 0 TD .3922 Tc [(Lo)392.2(f)4.1(p)392.2(l)412.9(a)392.2(s)412.1(m)392.2(aw)392.2(i)412(t)392.2(h)]TJ -17.1236 -1.1174 TD 0 Tc (50)Tj /F9 1 Tf 1.1462 0 TD (m)Tj /F3 1 Tf .5472 0 TD [(L)-324.8(o)0(f)-318.9(P)0(B)20(S)0(,)-315.4(i)0(n)-313.3(a)0(d)13.9(d)0(i)20.7(t)0(i)20.6(o)0(n)-313.2(t)0(o)-319.1(a)-324.8(se)14.1(pa)19.7(ra)19.7(te)-314.5(sa)14.1(mp)19.6(le)-314.5(of)-318.9(0.)24.3(5)]TJ /F9 1 Tf 20.1244 0 TD (m)Tj /F3 1 Tf .5472 0 TD .3249 Tc [(mo)324.9(f)]TJ -22.3649 -1.1116 TD 0 Tc [(Al)14.1(ex)19.7(a-)19.7(48)20.8(8-)20.9(la)19.5(be)19.7(le)19.6(d)-444.6(A)0(S)20.1(O)-439.7(in)-428.5(PB)20(S)-438.7(t)0(o)-434.3(d)0(e)19.7(t)0(e)19.6(r)0(m)19.7(i)0(n)20.7(e)-440(th)20.7(e)-440(r)0(e)14(t)0(e)19.6(n)0(t)20.7(i)0(o)20.7(n)]TJ T* [(ti)14.8(m)15(e)-273(of)-261.4(th)20.7(e)-273(l)0(a)19.5(b)0(e)19.7(l)0(.)]TJ 1.0137 -1.1174 TD [(To)-233.8(st)20.9(ud)20.8(y)-248.8(t)0(h)20.7(e)-244.2(pr)20.9(ot)20.7(ei)19.5(n)-243(b)0(i)20.7(n)0(d)20.8(i)0(n)20.7(g)-243(ch)19.7(ar)19.7(ac)18.5(te)19.6(ri)20.7(st)26.7(ic)19.6(s)-248.6(o)0(f)-232.6(t)0(h)20.7(e)-249.9(AS)20.1(O)-243.9(b)0(e)19.7(-)]TJ -1.0137 -1.1116 TD [(tw)19.8(ee)18.5(n)-248.8(s)0(a)19.9(m)0(p)25.4(l)0(e)19.5(s)0(,)-240.5(5)0(0)]TJ /F9 1 Tf 7.4012 0 TD (m)Tj /F3 1 Tf .5414 0 TD [(L)-244.2(o)0(f)-238.3(a)-249.9(1.)18.5(0)]TJ /F9 1 Tf 4.0145 0 TD (m)Tj /F3 1 Tf .5357 0 TD [(M)-249.7(o)0(f)-238.3(I)0(O)20(N)0(-)20(4)0(0)20.8(7)0(9)20.8(8)0(8)-238.3(w)15.3(as)-239.3(sp)21(ik)20.7(ed)]TJ -12.4928 -1.1116 TD [(in)20.7(to)-140.6(50)]TJ /F9 1 Tf 2.828 0 TD (m)Tj /F3 1 Tf .5414 0 TD .0118 Tc [(L)-140.2(o)11.8(f)-128.6(b)11.8(o)32.6(t)11.8(h)-128.8(W)11.8(T)34.9(/)11.8(W)30.3(T)-140.2(a)11.8(n)31.5(d)-139(H)11.8(O)30.9(/)11.8(H)37.4(O)-145.7(p)4.9(l)-.9(asma.)-158.7(I)-.8(n)-162.1(a)3.8(dd)4.9(it)4.8(ion)4.9(,)-164.4(t)4.8(o)]TJ -3.3694 -1.1116 TD .0131 Tc [(stu)6.2(d).5(y)-425.7(t)6.1(he)-426.9(A)5.4(S).6(O)-426.6(b).5(i)6.1(n).5(d)6.2(i).4(ng)-425.7(d)6.2(i).4(s)6.4(p).5(la)5.1(ce)5.1(me)5.1(nt)6.1(,)-428.1(a)-426.9(n)6.2(onl)6.1(ab)6.2(el)6.1(ed)-425.7(A)5.4(S).7(O)]TJ 0 -1.1174 TD .0123 Tc [(\(ION-)5.5(353)5.4(38)5.4(2\))-230.7(was)-230.5(p)5.4(rep)5.4(a)-1.5(r)5.5(e)-1.5(d)-230.7(a)4.3(nd)-230.7(2)5.4(5)]TJ /F9 1 Tf 14.6642 0 TD 0 Tc (m)Tj /F3 1 Tf .5587 0 TD .2442 Tc [(Lo)231.6(f)7(a)0(2)231.6(.)235(0)]TJ /F9 1 Tf 4.0836 0 TD 0 Tc (m)Tj /F3 1 Tf .5587 0 TD .0069 Tc [(M)-237(s)-5.5(ol)-5.8(ut)-5.8(i)-5.8(o)0(n)]TJ -19.8652 -1.1116 TD .0124 Tc [(was)-178.6(a)4.4(dd)5.5(ed)-173(t)5.4(o)-173(25)]TJ /F9 1 Tf 6.543 0 TD 0 Tc (m)Tj /F3 1 Tf .5645 0 TD .186 Tc [(Lo)173.4(fa)5.2(2)173.4(.)176.8(0)]TJ /F9 1 Tf 3.9108 0 TD 0 Tc (m)Tj /F3 1 Tf .5587 0 TD .0126 Tc [(M)-173.7(s).2(ol)5.6(ut)5.6(io)5.7(n)-172.8(o)12.6(f)-145.1(I)12.6(O)32.6(N)12.6(-)32.6(4)12.6(0)27.7(7)12.6(9)33.4(8)12.6(8)33.4(,)-152.1(b)12.6(o)33.4(t)12.6(h)]TJ -11.577 -1.1116 TD 0 Tc [(sp)15.3(ik)20.7(ed)-279.8(in)15(to)-278.8(50)]TJ /F9 1 Tf 5.8288 0 TD (m)Tj /F3 1 Tf .5414 0 TD -.0197 Tc [(L)-315.7(o)-19.7(f)-304.1(p)-19.7(la)-19.7(sm)-19.7(a.)-311.1(A)-19.7(l).1(l)-314.7(s)-19.7(am)-19.7(p)-28.9(l)-38.2(e)-39.2(s)-337.4(w)-38.9(e)-39.2(r)-38(e)-344.5(i)-38.2(n)-38.1(c)-39.2(u)-38.1(b)-38.1(a)-39.2(t)-38.2(e)-39.2(d)-337.6(a)-39.2(t)]TJ -6.3702 -1.1174 TD .0184 Tc (37)Tj /F8 1 Tf 1.0367 0 TD 0 Tc ()Tj /F3 1 Tf .4147 0 TD .0183 Tc [(C)-387(f)0(or)-385.9(30)-167.1(min)-386(b)-.1(efore)-387.1(a)-1.2(nalysis)-385.8(b)-.1(y)-386(H)-.9(PLC-SEC.)-388.3(An)-386(iso-)]TJ -1.4514 -1.1116 TD .0186 Tc [(cratic)-358(method)-356.9(was)-356.7(s).4(etup)-356.9(using)-356.9(a)-358(ow)-352(r)-5.5(ate)-358(o).2(f)-356.8(1).2(.0)-161(mL/min)]TJ T* .0183 Tc [(with)-155.6(PBS)-155.4(a)-1.2(s)-161.2(t)-.2(he)-156.7(mobile)-156.7(phase)-156.7(us)-5.6(ing)-155.6(a)-1.2(n)-155.6(\()0(300)]TJ /F8 1 Tf 17.6765 0 TD 0 Tc ()Tj /F3 1 Tf .7315 0 TD .0196 Tc [(4.6)-165.8(mm,)-150.9(3)]TJ /F9 1 Tf 4.1815 0 TD 0 Tc (m)Tj /F3 1 Tf .5702 0 TD .0196 Tc (m\))Tj -23.1598 -1.1174 TD .0187 Tc [(SEC)-282.9(c)-.8(olumn,)-278.5(with)-281.9(a)-277.3(2).3(5)]TJ /F9 1 Tf 9.924 0 TD 0 Tc (m)Tj /F3 1 Tf .5702 0 TD .0187 Tc [(L)-283.1(i).2(njection)-276.1(volume)-283.1(a)-.8(nd)-281.9(a)-277.3(20-min)]TJ -10.4942 -1.1116 TD 0 Tc [(r)-18.3(u)-18.4(n)-18.4(t)-18.5(i)-18.5(m)-19.6(e)-19.5(.)-827.1(F)-18.2(l)-18.5(u)-18.4(o)-18.4(r)-18.3(e)-19.5(s)-18.2(c)-19.5(e)-19.5(n)-18.4(c)-13.8(e)-825.9(e)-19.5(x)-18.4(c)-19.5(i)-18.5(t)-18.5(a)-19.5(t)-18.5(i)-18.5(o)-18.4(n)-18.4(/)-18.5(em)18.5(is)20.9(si)20.9(on)-785.5(wa)18.8(ve)13.9(le)19.6(ng)20.8(th)20.7(s)]TJ T* -.0204 Tc [(w)-20.4(e)-1.6(r)-20.4(e)-398.1(s)-20.4(e)-.5(t)-401.8(t)-20.4(o)-397.1(4)-20.4(95)-20.4(/5)-20.4(19)-177(n)-20.4(m)-.8(,)-404(w)-20.4(it)-20.4(h)-397.1(e)-20.4(nd)-20.4(og)-20.4(en)-20.4(ou)-20.4(s)-396.8(b)-20.4(ac)-20.4(kg)-20.4(ro)-20.4(un)-20.4(d)-397()-20.4(uo)-20.4(-)]TJ 0 -1.1174 TD 0 Tc [(re)14(sc)19.9(en)19.7(ce)-292.5(of)-295.9(pl)20.7(as)19.9(ma)-292.6(sa)19.9(mp)19.6(le)19.6(s)-306.2(s)0(u)21(b)0(t)20.7(r)0(a)14(c)0(t)19.5(e)0(d)-291.3(o)-12.6(u)-6.9(t)-323.8(o)-12.6(f)-323.6(t)-7(h)-12.6(e)-324.8(c)-8(h)-12.6(r)-6.8(o)-12.6(m)-8.1(a)-13.8(t)-7(o)-12.6(-)]TJ 0 -1.1116 TD .0124 Tc [(gram)-249.1(t)-.3(o)-247.9(e)4.4(xp)5.5(lo)5.5(re)-249(AS)5.7(O-)5.6(pro)5.5(tein)-247.9(b)5.5(i)-.3(nd)5.5(in)5.5(g)-247.9(i)-.3(nt)5.4(er)5.6(actio)5.5(ns)5.7(.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 310.8472 725.7825 Tm 0 Tc [(Total)-331.1(protein,)-333.7(albumin,)-339.3(immunoglobulins,)]TJ 0 -1.2203 TD [(and)-329.4(HRG)-337.5(quantitation)]TJ /F3 1 Tf 9.843 0 0 9.843 320.8251 698.3998 Tm [(Total)-307.6(protein)-314.4(content)-309.8(from)-310.8(WT/WT)-312.1(and)-309.7(HO/HO)-314.4(samples)]TJ -1.0137 -1.1174 TD (\()Tj /F7 1 Tf .3341 0 TD (n)Tj /F8 1 Tf .6624 0 TD (=)Tj /F3 1 Tf .72 0 TD [(7)-283.3(each\))-285.4(was)-281.6(assaye)-9.7(d)-277.6(using)-287.7(a)-278.7(Bradford)-287.4(Total)-284.6(Protein)-285.4(As-)]TJ -1.7164 -1.1116 TD [(say)-217.4(with)-212.9(samples)-218.4(diluted)-222.4(to)-215.4(t)-215.3(a)-215.4(curve)-215.1(range)-220.9(of)-215.3(1.510)]TJ /F9 1 Tf 21.5586 0 TD (m)Tj /F3 1 Tf .5529 0 TD (g/mL)Tj -22.1115 -1.1116 TD [(using)-391.3(an)-395(absorbance)-395.6(wavelength)-395.8(of)-393.8(595)-170.3(nm.)-392.8(Albumin,)-393.7(Im-)]TJ 0 -1.1174 TD [(munoglobulin)-504.4(G,)-500.7(M,)-506.5(and)-505.6(A,)-500.7(and)-505.6(HRG)-507.2(were)-502.9(assayed)-511.9(by)]TJ 0 -1.1116 TD [(murine-specic)-286.1(ELISA)-279.3(kits.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 310.8472 619.6534 Tm [(Plasma)-333.7(proteome)-332.9(ngerprinting)-335.7(by)-332.7(isoelectric)]TJ 0 -1.2203 TD [(focusing)-333.4(and)-329.4(SDS-PAGE)]TJ /F3 1 Tf 9.843 0 0 9.843 320.8251 592.2708 Tm [(The)-524(same)-531.9(volume)-527.5(\(60)]TJ /F9 1 Tf 9.7109 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L\))-527.5(from)-529.7(WT/WT)-525.2(and)-528.6(HO/HO)]TJ -11.2775 -1.1116 TD [(murine)-348.9(plasma)-355.7(samples)-350.8(was)-356.5(mixed)-347.9(with)-351.1(180)]TJ /F9 1 Tf 18.529 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-347.9(o)0(f)-347.8(binding)]TJ -19.0819 -1.1116 TD [(buffer)-324.5(followed)-327.9(by)-324.7(albumin/IgG)-326.8(removal.)-325.8(A)-324.5(200)]TJ /F9 1 Tf 20.0092 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-324.8(diluted)]TJ -20.5622 -1.1174 TD [(mixture)-350.2(containing)-347.8(50)]TJ /F9 1 Tf 9.227 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-347.9(o)0(f)-347.7(depleted)-346.6(plasma)-349.9(was)-350.7(added)-353.4(to)]TJ -9.78 -1.1116 TD (150)Tj /F9 1 Tf 1.6646 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(L)-445.8(o)0(f)-445.7(two-dimensional)-453.2(rehydration)-446.6(media)-452.7(per)-442.2(sampl)-7.8(e)]TJ -2.2175 -1.1116 TD [(and)-298.2(loaded)-302.8(onto)-298.3(a)-296(11-cm)-301.6(ReadyStrip)-302.4(IPG)-297.7(for)-302.7(separation)-302.5(be-)]TJ 0 -1.1174 TD [(tween)-383.2(pH)-389(3)-381.2(and)-384.6(10)-388.1(for)-383.4(16)-169.2(h.)-378.9(Isoele)-8.8(ctric)-382.4(focusing)-390(was)-385.3(per-)]TJ 0 -1.1116 TD [(formed)-193.2(by)-198(a)-192.3(rapid)-196.8(ramp)-196.8(at)-193.6(200)-170.3(V)-192(for)-193.3(the)-200.4(rst)-194.2(step,)-193.2(followed)-201.1(by)]TJ T* [(a)-215.4(gradual)-223.3(ramp)-219.9(to)-215.4(8,000)-169.1(V)-215.1(t)0(o)-221.2(1)-162.4(h)-220(and)-217.6(maintained,)-221.1(followed)-224.2(by)]TJ 0 -1.1174 TD [(a)-376.6(hold)-373.2(at)-377.9(1,500)-163.3(V)-376.3(using)-374.1(a)-376.6(Protean)-378.6(i12)-377.8(IEF)-372.9(Cell)-375.5(\(Bio-Rad\).)]TJ 0 -1.1116 TD [(Following)-333.6(isoelectric)-339.6(focusing,)-335.9(the)-332.9(second)-337(dimension)-334.9(SDS-)]TJ T* [(polyacrylamide)-488.2(gel)-476.9(electrophoresis)-487.7(\(PAGE\))-487.4(was)-483.2(prepared)]TJ 0 -1.1174 TD [(using)-702.4(a)-704.9(precast)-708(8%16%)-705.7(Tris-HCl)-708.8(gel)-701.5(of)-704.9(dimensions)]TJ 0 -1.1116 TD (13.3)Tj /F8 1 Tf 1.918 0 TD ()Tj /F3 1 Tf .7142 0 TD [(8.7)-166.9(cm)-327.1(\(width)]TJ /F8 1 Tf 5.7539 0 TD ()Tj /F3 1 Tf .72 0 TD [(length\))-320.1(and)-327(run)-320.1(at)-326(150)-164.6(V)-324.5(constant)-328(for)]TJ -9.1061 -1.1116 TD [(110)-164.6(min)-402.1(using)-402.9(a)-405.4(Bio-Rad)-408.5(model)-399.7(PWSPL-4)-408.1(electrophoresis)]TJ T* [(power)-341.6(supply.)-338.3(The)-339.7(gel)-338.7(was)-345(then)-339.8(stained)-338.4(by)-342(coomassie)-342.7(blue)]TJ 0 -1.1174 TD [(staining)-298.1(using)-299.2(SimplyBlue)-296.9(SafeStain)-301.3(with)-299.3(imaging)-298.3(acquired)]TJ 0 -1.1116 TD [(by)-405.4(an)-406.5(ImageQuant)-408.4(LAS)-408.4(4000)-407.6(system)-406.2(\(GE)-408.5(Healthcare)-415.4(Bio)]TJ T* [(Sciences,)-327.7(Marlborough,)-328.7(MA\).)-325.3(Relevant)-330.4(bands)-323.3(were)-330.1(excised)]TJ 0 -1.1174 TD [(and)-298.2(characterized)-304.9(by)-295.9(LC-MS)-296.4(based)-301.4(on)-295.9(coverage,)-299.1(number)-302.7(of)]TJ 0 -1.1116 TD [(unique)-278.6(peptides,)-285.3(molecular)-285.6(weight,)-283(and)-280.9(isoelectric)-282(point.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 310.8472 349.1716 Tm [(Statistical)-336.1(analysis)]TJ /F3 1 Tf 9.843 0 0 9.843 320.8251 332.7306 Tm [(Statistical)-511.4(signicance)-512(between)-513.3(samples)-506.3(was)-512(evaluated)]TJ -1.0137 -1.1116 TD [(using)-506.5(analysis)-506.3(of)-509(variance)-508.9(and)-511.3(Students)]TJ /F7 1 Tf 17.9012 0 TD (t)Tj /F3 1 Tf .2822 0 TD [(-test.)-511.2(Mean)-508.7(of)]TJ -18.1834 -1.1116 TD [(replicate)-239.5(measurements)-238.9(\()]TJ /F7 1 Tf 10.0104 0 TD (n)Tj /F8 1 Tf .6681 0 TD (=)Tj /F3 1 Tf .7142 0 TD [(4\))-238.3(per)-234.8(group)-235.9(with)-230.2(corresponding)]TJ -11.3927 -1.1174 TD [(standard)-183.8(deviation)-191.2(values)-181.7(was)-189.5(used)-183.9(to)-186.6(plot)-183.2(the)-183.1(gures.)-189.4(Sample)]TJ 0 -1.1116 TD [(group)-281.9(differences)-293.1(less)-281.8(than)]TJ /F7 1 Tf 11.1565 0 TD (P)Tj /F8 1 Tf .7776 0 TD (<)Tj /F3 1 Tf .72 0 TD [(0.05)-283.2(were)-289.8(determined)-286.7(as)-285.4(sta-)]TJ -12.6541 -1.1116 TD [(tistically)-284.6(signicant.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 310.8472 254.0409 Tm (Results)Tj /F10 1 Tf 0 -1.8336 TD [(Plasma)-333.7(and)-335.7(tissue)-330.8(PKs)]TJ /F3 1 Tf 9.843 0 0 9.843 320.8251 221.159 Tm [(Pl)20.9(as)14.1(ma)-453.8(tr)15(ou)15.1(gh)-451.5(AS)14.4(O)-462.7(c)0(o)19.7(n)0(c)13.9(e)0(n)13.9(t)0(r)15(a)0(t)13.8(i)0(o)15(n)0(s)-451.3(w)0(e)13(r)0(e)-452.6(d)0(e)13.9(t)0(e)19.5(r)0(m)13.9(i)0(n)15(e)0(d)-452.6(b)0(y)]TJ -1.0137 -1.1116 TD [(EC)18.6(L-)13.9(EL)12.7(IS)15.3(A,)-172.4(wh)14.2(il)14.8(e)-180.8(l)0(i)14.8(v)0(e)13.9(r)-179.6(an)13.9(d)-185.4(k)0(i)20.7(d)0(n)15.1(e)0(y)-176.2(A)0(S)14.4(O)-180.5(co)13.9(nc)13.9(en)13.9(tr)15(at)19.5(io)14.9(ns)-174.8(we)13.1(re)]TJ T* [(de)13.9(te)19.6(rm)13.9(in)15(ed)-314.4(by)-313.2(LC)12.9(-M)20(S)-323.5(a)0(t)-314.5(7)0(2)-152(h)-317.9(fo)15.1(ll)14.8(ow)14.2(in)14.9(g)-317.9(s)0(i)15.1(n)0(g)15.1(l)0(e)-314.5(s)0(.)18.7(c)0(.)-316.7(d)0(o)15.1(s)0(e)-314.2(a)0(d)19.7(-)]TJ 0 -1.1174 TD [(mi)13.7(ni)20.7(st)15.1(ra)14(ti)14.8(on)-272.9(of)-272.9(IO)20(N-)14.2(35)15.1(33)15.1(82)15.1(.)-279.9(L)0(o)13.9(g)-277.6(tr)15(an)13.9(sf)15.3(or)15.1(me)18.4(d)-277.6(p)0(l)14.9(a)0(s)14.1(m)0(a)-275.3(C)]TJ 7.3823 0 0 6.5614 530.9857 186.633 Tm [(tr)22.7(ou)17(gh)]TJ 9.843 0 0 9.843 310.8472 177.3354 Tm [(va)13.9(lu)15(es)-314.2(ar)14(e)-324.8(l)0(i)14.8(s)0(t)15.1(e)0(d)-314.4(i)0(n)-313.4(F)0(i)15.1(g)0(.)-315.6(1)0(A)14.2(,)-320.2(wi)14.1(th)-319.1(er)14(ro)20.9(r)-323.6(b)0(a)13.9(r)0(s)-318.8(r)0(e)14(p)0(r)15.1(e)0(s)14.1(e)0(n)19.7(t)0(i)14.8(n)0(g)-319(t)0(h)20.7(e)]TJ 0 -1.1116 TD [(st)15.1(an)13.9(da)19.7(rd)-146.2(de)13.9(vi)14.9(at)19.5(io)15(n)-150.8(f)0(r)15.1(o)0(m)-141.7(\()]TJ /F7 1 Tf 9.7166 0 TD (n)Tj /F8 1 Tf .6566 0 TD (=)Tj /F3 1 Tf .7142 0 TD [(4\))-140.4(an)13.9(im)13.7(al)13.8(s.)-142.6(Pl)15.1(as)14.1(ma)-142.8(co)13.9(nc)19.7(en)13.9(tr)15(at)13.8(io)15(ns)]TJ -11.0874 -1.1174 TD [(of)-249.8(AS)14.4(O)-261.2(s)0(p)15.3(a)0(n)13.9(n)0(e)13.9(d)-260.3(fr)15.1(om)-251.1(a)-261.4(r)0(a)13.9(n)0(g)15.1(e)-261.4(of)-249.8(1.)12.7(8)15.1(22)15.1(.2)-148.5(ng)15.1(/m)13.7(L)-261.5(a)0(c)18.5(r)0(o)15.1(s)0(s)-255.2(d)0(o)15.1(s)0(e)]TJ 0 -1.1116 TD [(gr)15.1(ou)15.1(ps)15.3(.)-158.9(A)-157.5(do)15.1(se)14.1(-d)15.1(ep)13.9(en)13.9(de)13.9(nt)-152.1(up)15.1(ta)19.6(ke)-158.9(an)19.7(d)-162.4(A)0(S)14.4(O)-163.2(ex)19.7(po)15.1(su)15.3(re)-153.1(in)-152.1(pl)14.9(as)14.1(ma)]TJ T* [(we)13(re)-176.1(ob)15.1(se)14.1(rv)15.1(ed)-176.2(ac)12.8(ro)15.1(ss)-180.4(th)15(e)-186.6(5)0(,)-177.3(1)0(5)15.1(,)-182(30)15.1(,)-187.7(a)0(n)13.9(d)-185.4(60)-152(mg)19.6(/k)15(g)-185.4(d)0(o)15.1(s)0(e)-181.7(c)0(o)13.9(h)0(o)20.8(r)0(t)15(s)0(.)]TJ 0 -1.1174 TD [(Sl)15.1(op)15.1(es)-170.2(fr)15.1(om)-170.5(th)15(e)-180.8(l)0(i)14.8(n)0(e)19.7(a)0(r)14(i)0(z)13.8(e)0(d)-170.4(l)0(o)15(g)0(-)15.1(t)0(r)15(a)0(n)13.9(s)0(f)15.3(o)0(r)15.1(m)0(e)12.7(d)-179.6(C)]TJ 7.3823 0 0 6.5614 483.7038 120.8692 Tm [(tr)22.7(ou)17(gh)]TJ 9.843 0 0 9.843 504.3967 122.5133 Tm [(va)13.9(lu)15(es)-170.2(we)13.1(re)]TJ -19.6636 -1.1116 TD [(1.)18.5(02)-175(an)19.7(d)-179.6(0)0(.)12.7(6)0(9)-169.2(f)0(o)15.1(r)-179.6(WT)17.4(/W)12.7(T)-180.8(a)0(n)13.9(d)-179.6(HO)19.1(/H)14.1(O)-180.5(t)0(y)15(p)0(e)13.9(,)-176.2(re)14(sp)15.3(ec)12.8(ti)14.8(ve)13.9(ly)15(,)-176.2(w)0(i)14.1(t)0(h)]TJ T* [(co)13.9(ef)19.7(c)14.1(ie)13.8(nt)-676.2(of)-670.3(de)13.9(te)13.8(rm)13.9(in)20.7(at)13.8(io)15(n)-680.7(\()0(R)]TJ 7.3823 0 0 6.5614 443.792 104.9953 Tm (2)Tj 9.843 0 0 9.843 447.4203 100.6299 Tm .6807 Tc [(\)v)680.7(a)694.6(l)680.7(u)695.7(e)680.7(s)9.4(\()]TJ /F8 1 Tf 4.5444 0 TD 0 Tc (>)Tj /F3 1 Tf .5414 0 TD [(0.)12.7(99)15.1(\).)-672.6(Do)20(se)14.1(-)]TJ -18.9609 -1.1174 TD [(pr)15.1(op)15.1(or)15.1(ti)20.6(on)15.1(al)-182(pl)14.9(as)14.1(ma)-177.4(C)]TJ 7.3823 0 0 6.5614 396.5101 88.0441 Tm [(tr)15(ou)17(g)16.2(h)0(s)]TJ 9.843 0 0 9.843 420.0944 89.6314 Tm [(we)13(re)-176.1(ob)15.1(se)14.1(rv)15.1(ed)-176.2(fo)15.1(r)-191.1(W)0(T)17.4(/)0(W)12.7(T)0(,)-178.5(w)0(h)14.2(i)0(l)14.8(e)]TJ -11.0989 -1.1116 TD [(sl)15.1(ig)15(ht)14.9(ly)-232.7(le)13.8(ss)-232.2(th)15(an)-233.8(do)15.1(se)-239.3(pr)20.9(op)15.1(or)15.1(ti)14.8(on)15.1(al)-233.9(in)-238.5(HO)19.1(/H)14.1(O)-243.9(m)0(i)13.7(c)0(e)12.8(.)]TJ 1.0137 -1.1116 TD [(Exposure)-195.3(of)-198(ASO)-195(in)-198.2(tissue,)-201.1(including)-195.8(both)-200.4(liver)-197(and)-194.5(kidney)]TJ -1.0137 -1.1116 TD [(evaluations,)-324.5(is)-318.9(described)-318.6(in)-319.1(Fig.)-323.5(1B)-320(and)-315.5(C.)-322.3(Dose-dependent)]TJ /F4 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(PK/PD)-340.1(OF)-331.2(ION-353382,)-332.4(A)-337.9(MODEL)-333.5(ASO:)-334.7(IN)-335.1(WT)-335.9(AND)-330.9(DKO)-337.5(MICE)-23255.2(227)]TJ ET endstream endobj 105 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 62.022 336.1889 Tm 0 0 0 rg 0 Tc 0 Tw [(uptake)-567.8(was)-569.6(observed)-563.8(for)-567.7(groups)-565.1(across)-567.2(the)-569(dose)-564.1(range.)]TJ 0 -1.1116 TD [(Concentrations)-221.7(of)-215.3(ASO)-212.2(in)-215.4(the)-211.9(liver)-220(spanned)-217.2(a)-215.4(range)-215.1(from)-212.9(2)-214.2(t)0(o)]TJ 0 -1.1174 TD (16)Tj /F9 1 Tf 1.1692 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/g,)-191.2(with)-189.8(higher)-192.2(exposure)-195.2(levels)-193.3(in)-192.4(kidney)-192.2(ranging)-187.5(from)-195.6(7)]TJ -1.7222 -1.1116 TD [(to)-330.6(33)]TJ /F9 1 Tf 2.2751 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/g)-326(across)-331.1(dose)-333.7(groups.)-326.6(Log)-327(transformat)-9.9(ions)-326.9(of)-324.7(liver)]TJ -2.828 -1.1116 TD [(uptake)-239.5(revea)-9(led)-235(slightly)-245.3(less)-241.5(than,)-239.5(but)-239.6(near)-242.8(dose)-241.5(proportional)]TJ 0 -1.1174 TD [(liver)-387(uptake,)-381.1(with)-385.7(slopes)-387.6(of)-382.3(0.84)-381.1(and)-384.6(0.80,)-384.6(\(R)]TJ 7.3823 0 0 6.5614 250.4692 285.7889 Tm (2)Tj /F8 1 Tf 9.843 0 0 9.843 255.8551 281.3669 Tm (>)Tj /F3 1 Tf .7142 0 TD [(0.99\),)-385.6(for)]TJ -20.4066 -1.1116 TD [(WT/WT)-369.7(and)-367.3(HO/HO)-372(mice,)-368.6(respectivel)-11.2(y.)-367.4(The)-368.5(same)-364.9(assess-)]TJ T* [(ment)-329.5(in)-324.9(kidney)-330.4(revealed)-330.3(less)-327.9(than)-328.2(dose)-327.9(proportional)-331.5(kidney)]TJ T* [(exposure)-310.4(with)-305(slopes)-312.8(of)-307.4(0.50)-306.2(and)-304(0.55,)-309.7(\(R)]TJ 7.3823 0 0 6.5614 230.0598 252.907 Tm (2)Tj /F8 1 Tf 9.843 0 0 9.843 235.4456 248.5417 Tm (>)Tj /F3 1 Tf .7142 0 TD [(0.98\),)-310.7(for)-302.7(WT/)]TJ -18.3331 -1.1174 TD [(WT)-380(and)-378.8(HO/HO,)-381.2(respectively.)-384.3(Kidney)-377.4(to)-376.7(liver)-381.3(ratios)-376.4(were)]TJ 0 -1.1116 TD [(between)-467.2(2)-467.6(and)-465.2(5)-461.9(across)-463.5(dose)-466.1(groups,)-464.8(and)-465.2(ratios)-468.6(between)]TJ T* [(groups)-305.9(were)-312.8(superimposable)-313.7(and)-309.7(near)-306.2(identical)-313.4(with)-305(no)-307.5(sta-)]TJ 0 -1.1174 TD [(tistically)-284.6(signicant)-284.1(differences.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 62.022 182.7779 Tm [(PD)-335.8(effect)-335.1(following)-331.1(ASO)-340.3(treatment)]TJ /F3 1 Tf 9.843 0 0 9.843 72 166.3369 Tm [(PD)-550.1(effect)-557.3(was)-552.3(evaluated)-556.2(by)-555.1(measuring)-554.8(SRB1)-553.5(mRNA)]TJ -1.0137 -1.1174 TD [(knockdown)-455.5(in)-451.6(both)-448(WT/WT-)-457.1(and)-453.7(HO/HO-derived)-458.1(organs)]TJ 0 -1.1116 TD [(and)-263.7(comparing)-267(treated)-264.8(animal)-269.6(expression)-266.5(to)-261.5(the)-263.8(saline)-262.4(dosed)]TJ T* [(control.)-438.8(Following)-437.2(treatment,)-438.9(the)-436.6(PD)-434.9(effect)-436.4(of)-434.1(ASOs)-437.8(was)]TJ T* [(signicantly)-418.9(different)-421.3(across)-417.4(various)-412(tissues,)-420.9(including)-414.6(the)]TJ 0 -1.1174 TD [(liver,)-327.1(heart,)-328.1(kidney,)-322.4(quadriceps,)-328.9(jejunum,)-324.8(and)-327(lung)-321.3(\(Fig.)-324.6(2\).)]TJ 0 -1.1116 TD [(Control)-469.8(saline)-469.8(mRNA)-469.2(expression)-473.8(levels)-469.8(are)-466.4(listed)-468.7(with)-472.1(a)]TJ T* [(dashed)-383.1(bar)-378.8(representative)-384.2(of)-376.5(0%)-377.6(target)-377.8(knockdown)-380.6(\(no)-377.6(ef-)]TJ 0 -1.1174 TD [(fect\).)-316.6(Clear)-320(differences)-321.9(between)-317.5(tissues)-319.6(were)-318.6(observed)-316.2(with)]TJ 0 -1.1116 TD [(the)-574.8(most)-575.8(evident)-580.5(effect)-580.4(in)-572.5(liver,)-580.5(in)-572.5(addition)-574.8(to)-578.3(notable)]TJ T* [(knockdown)-334.5(in)-330.6(the)-327.1(kidney)-330.4(and)-332.8(heart,)-333.9(with)-328.1(minimal)-334.3(effect)-332.7(in)]TJ 25.504 28.3896 TD [(the)-321.4(jejunum)-315.6(and)-315.5(lung.)-313.2(A)-313(dose-depend)-9.6(ent)-315.6(PD)-313.9(effect)-315.4(was)-316.2(ob-)]TJ 0 -1.1116 TD [(served)-365.8(in)-365.2(the)-361.7(liver)-364(ranging)-366.1(from)-362.7(16%)-361.5(to)-365.2(93%)-361.5(inhibition)-363(of)]TJ 0 -1.1174 TD [(target)-446.9(expres)-8.7(sion.)-439.8(By)-446.7(expression)-450.8(levels)-446.7(alone,)-443.4(statistically)]TJ 0 -1.1116 TD [(signicant)-364.7(differences)-362.2(\()]TJ /F7 1 Tf 9.6878 0 TD (P)Tj /F8 1 Tf .7833 0 TD (<)Tj /F3 1 Tf .7142 0 TD [(0.01)-358.1(to)]TJ /F7 1 Tf 3.2485 0 TD (P)Tj /F8 1 Tf .7833 0 TD (<)Tj /F3 1 Tf .7142 0 TD [(0.05\))-359.1(were)-358.9(observed)]TJ -15.9313 -1.1116 TD [(betwe)-8.8(en)-222.2(WT/WT)-225.7(and)-223.3(HO/HO)-222.2(mice,)-224.6(with)-224.4(1.3-,)-223.2(1.7-,)-223.2(2.0-,)-223.2(and)]TJ 0 -1.1174 TD [(1.9-fold)-287.7(enhanced)-289.9(efcacies)-291.9(for)-285.5(the)-286.8(HO/HO)-285.6(subtype)-291(at)-285.7(dose)]TJ 0 -1.1116 TD [(levels)-285.5(of)-278.6(5,)-281(15,)-282.1(30,)-282.1(and)-280.9(60)-163.5(mg/kg.)]TJ 1.0137 -1.1116 TD [(In)-376.5(addition,)-382.4(at)-377.9(higher)-382.2(ranging)-377.6(dose)-379.8(groups,)-378.4(ION-353382)]TJ -1.0137 -1.1116 TD [(was)-316.2(more)-317.8(efcacious)-320.7(in)-313.3(4/4)-314.5(other)-312(minor)-312.1(tissues)-319.6(for)-314.3(HO/HO)]TJ 0 -1.1174 TD [(mice.)-195.8(A)-186.3(more)-191.1(subtle)-192.1(pattern)-188.8(of)-186.5(improved)-195.6(PD)-187.2(for)-187.5(HO/HO)-193.4(mice)]TJ 0 -1.1116 TD [(was)-264.3(evident)-258(across)-261.9(all)-258.2(other)-254.4(tissues)-262(and)-257.9(at)-256.9(the)-258(15)-169.2(mg/kg)-260.3(dose)]TJ T* [(in)-324.9(the)-321.4(heart,)-316.6(and)-321.2(60)-169.2(mg/kg)-317.9(dose)-322.2(in)-319.1(kidney,)-322.4(HO/HO)-325.9(had)-321.2(sta-)]TJ 0 -1.1174 TD [(tistically)-394.1(signicant)-393.5(improved)-391.4(PD)-388.8(differences)-396.8(compared)-387.9(to)]TJ 0 -1.1116 TD [(WT/WT)-283.3(\()]TJ /F7 1 Tf 4.0203 0 TD (P)Tj /F8 1 Tf .7833 0 TD (<)Tj /F3 1 Tf .72 0 TD [(0.05\).)-276.2(Kidney,)-282.9(heart,)-282.1(quadriceps,)-282.8(jejunum,)-284.5(and)]TJ -5.5236 -1.1116 TD [(lung)-292.5(knockdown)-288.4(across)-290.7(dose)-287.6(groups)-294.4(was)-287.4(from)-287.8(17%)-292.4(to)-284.6(39%,)]TJ 0 -1.1174 TD [(5%)-383.4(to)-376.7(25%,)-382.2(0%)-383.4(to)-376.7(22%,)-382.2(0%)-377.6(to)-382.5(25%,)-376.4(and)-384.6(0%)-377.6(to)-382.5(20%,)-376.4(re-)]TJ 0 -1.1116 TD [(spectively.)-208.2(Using)-207.9(an)-204.9(inhibitory)-207.3(effect)-206(liver)-202.7(exposure)-206.7(response)]TJ T* [(PD)-682.6(model)-681.9(revealed)-687.4(a)-676.1(near)-686.3(2.0-fold)-679.3(enhanced)-681.6(efcacy)]TJ T* (\()Tj /F7 1 Tf .3341 0 TD (P)Tj /F8 1 Tf .7833 0 TD (<)Tj /F3 1 Tf .72 0 TD [(0.05\))-243.9(for)-245.1(HO/HO)-251(mice)-250(with)-247.4(simulated)-249.8(liver)-243(EC)]TJ 7.3823 0 0 6.5614 517.1526 137.3102 Tm (50)Tj 9.843 0 0 9.843 526.9605 138.9543 Tm (values)Tj -21.7314 -1.1174 TD [(equivalent)-504.5(to)-497.7(5.49)]TJ /F8 1 Tf 7.885 0 TD ()Tj /F3 1 Tf .72 0 TD [(0.95)-496.3(and)-499.8(2.85)]TJ /F8 1 Tf 6.111 0 TD ()Tj /F3 1 Tf .72 0 TD [(0.33)-496.3(\(Fig.)-497.3(3\).)-500.9(Model)]TJ -15.436 -1.1116 TD [(parameters)-287.5(are)-282.1(listed)-284.4(in)-278.8(Table)-285.6(2.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 313.0582 95.074 Tm (Immunohistochemistry)Tj /F3 1 Tf 9.843 0 0 9.843 323.0361 78.6331 Tm .0218 Tc [(IHC)-268.3(w)-3.2(as)-272.8(p)3.4(e)2.3(rf)3.5(or)3.5(med)-273(t)3.3(o)-273(e)2.3(val)3.3(u)-2.3(at)3.3(e)-274.2(A)2.6(S)3.6(O)-273.9(d)3.4(i)-2.5(s)3.6(t)-2.5(r)3.5(i)3.3(bu)3.4(t)3.3(i)-2.5(o)3.4(n)-273(i)3.3(n)-273(t)3.3(h)3.4(e)]TJ -1.0137 -1.1116 TD .019 Tc [(m)-6.4(ous)-4.9(e)-507.4(l).5(i)-5.3(v).6(er)-512(of)-506.2(b)-5.1(o).6(th)-512(WT/WT)-513.2(a)-.5(nd)-506.2(H)-6(O)-.2(/H)-6(O)-507.1(m)-.6(ic)-6.3(e.)-508.6(Cl)-5.3(ear)]TJ T* .0186 Tc [(m)-6.8(o).2(rp)-5.5(hol)-5.7(ogy)-287.8(rel)-5.7(a)-.9(te)-6.7(d)-282(t).1(o)-287.8(t).1(he)-288.9(liv)-5.5(er)-282(i)-5.7(s)-281.8(ob)-5.5(ser)-5.5(v).2(ed)-5.5(,)-284.3(i).1(nc)-6.7(lud)-5.5(i).1(ng)-287.8(the)]TJ ET q 1 i 191.622 732.019 m 552.189 732.019 l 552.189 366.69 l 191.622 366.69 l W n q 360.926 0 0 365.329 191.622 366.69 cm /Im1 Do Q Q BT /F5 1 Tf 9.845 0 0 9.845 62.022 645.5621 Tm 0 Tc [(FIG.)-647.7(1.)]TJ /F3 1 Tf 4.4283 0 TD [(Pla)13.1(sma)]TJ /F5 1 Tf 3.4321 0 TD (\(A\))Tj /F3 1 Tf 1.3705 0 TD [(,)-562(liv)19.7(er)]TJ /F5 1 Tf -9.2309 -1.0077 TD (\(B\))Tj /F3 1 Tf 1.3187 0 TD [(,)-458.3(and)-453.3(kid)14.1(ney)]TJ /F5 1 Tf 5.7758 0 TD (\(C\))Tj /F3 1 Tf 1.837 0 TD [(PKs)-446.9(of)]TJ -8.9315 -1.0135 TD [(ION)12.7(-35)14.3(338)14.3(2)-398.3(i)0(n)-399.5(W)0(T)12(/WT)-398.1(an)14.1(d)]TJ T* [(HO/)12.5(HO)-320.3(mi)14(ce.)-318.7(Mi)14.3(ce)-321(wer)12.3(e)-324.6(a)0(d)14.1(-)]TJ 0 -1.0077 TD [(min)13(ist)14.1(ere)12(d)-329.2(a)-336.2(sin)14.3(gle)-321(dos)14.5(e)-330.4(sub)14.5(-)]TJ 0 -1.0135 TD [(cut)13(ane)12(ous)-417.4(in)15.1(jec)11.8(tio)14(n)-427.1(a)0(t)-423.7(5)0(,)-419(15,)]TJ T* [(30)21.1(,)-153.1(a)0(n)19.9(d)-145(60)-151.7(m)15.1(g)0(/)15.1(k)0(g)21.1(.)-147.3(Cu)20.1(rv)21(es)-141.2(we)19.1(re)]TJ T* -.0196 Tc [(l)-19.6(o)1.3(g)-204.9(t)-19.6(ra)-19.6(ns)-19.6(fo)-19.6(rm)-19.6(ed)-204.9(a)-19.6(n).3(d)-204.9(l)-19.6(in)-19.6(ea)-19.6(ri)-19.6(ze)-19.6(d)]TJ 0 -1.0077 TD 0 Tc [(to)-284.3(de)14.1(te)19.7(rm)19.9(in)20.9(e)-295.9(d)0(o)21.1(s)0(e)-290.9(p)0(r)21.1(o)0(p)21.1(o)0(r)21.1(t)0(i)20.7(o)0(n)21.1(-)]TJ 0 -1.0135 TD [(al)19.7(it)20.7(y.)-177.1(A)-180.3(t)0(o)20.9(t)0(a)19.7(l)-185.4(of)-174.7(fo)21(ur)-174.7(mi)19.7(ce)-171.3(we)19.1(re)]TJ T* [(us)21.2(ed)-412(pe)14.1(r)-421.4(g)0(r)21.1(o)0(u)21.1(p)-421.4(pe)19.9(r)-421.4(d)0(o)21.1(s)0(e)14.3(,)-418(in)20.9(-)]TJ T* [(cl)19.7(ud)21.1(in)20.9(g)-565.3(a)-560.7(sa)20(li)20.7(ne)-556(co)19.9(nt)20.9(ro)21(l)-559.7(f)0(o)21(r)]TJ 0 -1.0077 TD [(ea)18.7(ch)-435(ty)20.9(pe)19.9(.)-441(A)0(l)20.1(l)-438.8(sa)14.3(mp)19.9(le)19.7(s)-438.5(w)0(e)19.1(r)0(e)]TJ 0 -1.0135 TD [(co)19.9(ll)20.7(ec)18.7(te)13.9(d)-381.1(7)0(2)-151.7(h)-381.1(fo)15.3(ll)20.7(ow)20.2(in)20.9(g)-386.8(d)0(o)21.1(s)0(-)]TJ T* [(in)20.9(g.)-228.9(Pl)21.1(as)14.3(ma)-228.9(C)]TJ 7.3837 0 0 6.5625 115.9937 504.4534 Tm [(tr)30.5(ou)24.9(gh)]TJ 9.845 0 0 9.845 137.1968 506.0975 Tm [(wa)19.1(s)-236.9(e)0(v)19.9(a)0(l)19.7(u)0(-)]TJ -7.6358 -1.0077 TD [(at)19.7(ed)-187.4(by)-180.5(EC)18.9(L-)19.9(EL)18.7(IS)21.2(A,)-189.5(an)19.9(d)-191(l)0(i)20.7(v)0(e)19.9(r)]TJ 0 -1.0135 TD .0131 Tc [(an)6.3(d)-275.8(k).6(id)6.3(ne)5.2(y)-281.6(s)6.5(am)5.2(pl)6.2(es)-275.6(we)5.2(re)-277(as)6.5(-)]TJ T* .0101 Tc [(sayed)-601.3(b)-2.4(y)-595.5(L)-3.6(C-MS.)-597.9(L)-3.6(C-MS,)]TJ T* .012 Tc [(li)5.1(qu)5.2(id)-202.1(ch)5.2(romatog)5.2(raphy)5.2(mas)5.4(s)]TJ 0 -1.0077 TD .0072 Tc [(s)-5.1(p).4(e)-6.5(c)-.7(t)-5.5(r)-5.3(om)-6.5(et)-5.5(ry)-5.3(;)-420.1(P).6(K)-6.1(s).6(;)-420.1(p)-5.3(ha)-6.5(rm)-6.5(a-)]TJ 0 -1.0135 TD .0119 Tc [(co)5.1(ki)5(netics.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm 0 Tc (228)Tj 46.1699 0 TD [(SHEMESH)-334(ET)-338.7(AL.)]TJ ET endstream endobj 107 0 obj <>stream AdobedC        s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjz?k*j`Zq" w9[O15۸.7.Y%>Y|ٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳg15t&VK0]f܎)A2S\qh^U\/g4**ʺ%,qFnmCդ~w=m'rw6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6C%kpݫZsi~]EDnܺdU,]2LMe} 1G*uqo!o_I I08,n5 +L͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͐9j}HU5L[)h )|*)S3k3~yOPmkISr eKw4}b(hSֵBH5;ffU/!UeoNrS'f͛6lٳf͛6lE0B;TrZ/6lٳf͛6lٰ3jzj1GYML#`KA*Jв0`рm|J}.QRIx~/z5:f֍8$Wh~́IqCUI*C-i<ָaj6Zu,d 4V^kݖmskdJ /HR;ӼZsjZ}֜^E" '>,|$uC#K97d{ ~qyQkME-u*N$(G'7Me1yEO'`}KJ2E7JHP6"6l(ז5-~ki#`iyJ{(g<;~hmGTk-Zٹi0ְ+9}/Y0I:QhYOژiDP~.1hje-|s%顬4O<}pݷ!i9sX 8u˒Mvj^iO\V2;z x%Zϗh7KİI4zVF$ٙQネ+NO\l_K^ŬRx&! ^L(4dzF4UcQN!ے9]{Z/%^Y^ūj9?4/Cߔb˾kK2 ch05MTpdDoo-*RWEK]abH}iHd"Ij^ѿ!~[ɫXKY/lntYP~n~aRΎGpi.24.846lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛"^{Jмy48}N`tWyL DZbz{=o,J~XiӅ3F"vHX nUw1f͛6lٰY>hVE&g-R#/OjW9ʿ'hvybɵkuhc14`FVVV#e՗<u0\%7*,$j۸?̓C}.9b`ȶVSPA v_{O٥z\]l[n98;ƞ9"mM^Rt(iٛ%ehPף{1s͘AT9<8}OQmc囇3 @`k!kz,,,(,l`Kk;dXP`ȷ^x-;K{{$z;ӌΗΰH%c6+PLUgcchqiˤ궺]ы S-۷O2&q"kY=OQ8E˛}sϞX_辅"15;E:qDK&\k!ޖ8(=}q̭͐[-isfm\I.p}1AMe6l&hS\Akwn|qQV-ϯTz&r9^b>c{hsr*_򩼥^j+_)~5c_.b grx' nQl3Ο~w:nw>%-^~#꽳Yfͅ4]2X⾼ UMUJ c}egsi:x::6#͛6ִFI㱼Kf:ኚ=ԏ>ߙ4 =RIm?[9$UNeIf4F>R;)*iD1}$E<㡾cbԤl"DVV3CQ@7ñ wM,QH +q(j?V% 9+†RʥYѷCZl٪' ?ebS}GGm?g5OMdӼK+)I dpeq#b:d,Zn#¤+In$ĎwQJo/khg#+"}El~hiVz.m.!g&( ڬCrS6߽QZ3Ou6ʎLJYŕ־=r{6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳdKjVG$%v4i'TTw9<7ɾpg^3EwqE#,R"-QC av]q:4^_6Z!JΑ[VV2P!xa'ξZagtѵĐ"<"e@@BH+ FumYduk ff4`B 62s@ʋ W < w*qY)눥q$G+Sx p«QeVx_q|a_=՛6l@=ߘ CoAa њ#nZ1~ʢkj: C[{=?TpOo'(Cqpd:aZw8ͱN7Jo% zUx4 y:P(e?v5ͩ൨.?+nW*H o4{+KF2zu'|4ꅖHrۺ(H Eqg^֞^u,lb]ѕױj4Z#GqEjsZ+ VF)Yv+ż29ieJxWNLKs6!lgIV?f+Q>yWz꺔:wP/(jRzh)隍ȹ-4s[HEB@eBZo2hZsHC,e:]= m/__o4$n xY$Odh!b'ɍƗ._y)zZ *\y?zߘ<ɦ^jAej>E6XI'ם<o[DIncX%(jv5E+jZK[/HԗMɹB20HV'g=ZyIZOw$W]+" "`g@ ]Hf2*J'JS/巓[tn7V X-(m|ٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛zucK[BY4FdZ[Spo0AGb.Ү \\ I-:9ANÈAj~QtknEFT B/% ;q?,.{-c6":d}ui'j~*9%Qj#ojq"'%]_BUAlٳg"Z=֡a6ȆHcaUG$l[}<וum7\"u[1z_ļJ9ztڍNZ}ͅh\ )9 Zd{P6nY.)!,4B:ᕷ|oMZk.k$E&1 ,NjS[\\zd5dmK5QDpzޣ4%WR-޺>j7V?Xmm`R*Z4fOw'$IdgUpFlٳf͛"w|#JI ҕ~tJ/gYj3ỹWmestPU` < nnG2B%RǪr:7?--SCӡ2Mui "FSN;Lcs)-׵da+Zoj#=Fx NO6[o{qxјEx$VX n}ZyK}bAUTk|Yɯjw(bmwS(Q;x/fuCٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳfͅa.4k8vv|__E>G^2 Į3F>")tEE*(T @^lٳfn\OMyO8Wzq[}`73!VRα >#z6lٱl젺W*+f͛65Y3! J;6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf?y˒C\ZpK"FA sČDjwm4[0I,r0lZVPtAAO ٳf͛)ȟt[[{'Eb$$nRٳf͛6lٳf͛6lٳf͛6lٰη=V֢[w L¼ARk199b|*L6zx*E'=+{Sv!k5R60QijUlٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳd{ Mu?$6s̗w6Ήf ;)i*OsN?+4>N֭9/!]:iI$ޢ eY^q8杪}:6lٳf0pƱF-ZEt'a͛6lٳf͛6lٳf͛6l_tEֵ9 Z~Ou"r ?Fs/MHw?Ft+yGFihҙf$+5Wħsc' x$a/,B3!~by[_Ӽgt#l!q"< Tysf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛$K+gv *$ M[ ռզS\ɘ(T6lٳfbBH v=sr:\,<> H olٳf͛6lٳf͛6lٳfuƛVhbUb<y;XL?gѭ+I1VWh&piZEvZu+ok f,h=ى?|C^ޯD7c9) 2jc_Ʒ~{ELWZI.Z9":oo}+Xy^E>`%m#]7NU9g%ǘ.#"1%a8)#*z*Msf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛dVRp W5=l: ٳf͛6y[fa[˞͛6lٳf͛6lٳf͛6lٳ?rt[]~~z^0jA٢<#H9=Oqh#^E! 7FX4fZwv̞|=)~ίKrE r^ N7ׯߒo? ʶ^k~{(XJyz`6;+~hƏ.յht.b"G,nIHTgWEo+[%9/!\ y,Yj]vQE ]V`59v|Kmo.zo6lٳf͛6lٳf͛6lٳ`-rPѯl_NH`u*(;UI|7(:]Pubdu44?wI~J+kuyVF lԭOϻy?(6Vz&Khh9v9~Yյy]={黛yζ\ܑ)xjTYyUz9Ưyu4'T};a~1'Tg/,e2ͷ+w(a\+(-.EWM*);S<[!eK և̞g|KשaUdAv I3cmy~Io<]ZuLA0n81y+Y055i\!S[䂇ʒRlE!ԼӨ!]4l–zeֿA΁8d3UKocgm%Ai:Sִ+LlbH`Cknh ,xI󗙭]S7]dpRv^|VcK]>X$[<zs^A󅯜`ԑKyHgPɹ]c$f͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf̈́^zկi<Σ4 ,2PHZFmOKQvgiX/˶/,0o?8֜.ItMxi͛#2̋̀%P #N ^d`֬'֯02 C7ku+c&Dn.dgnbxi2q4j\i7Al=F^6zuV Zob[y#De!`~`燿-gxdc&)Tar*=˛6lٳf͛6lٳf͍h8UUI:5Sim45 {|] e?WczqSQϡUnf[z:S|rUOέ7M{9D Vѳ[C< .@98iۙy/)__~ko=yy4HI )f~/@60~syQlos]'֮aD0rTgt,U?+-ΧkA}q}; 3E}1Slp䟕&vΕ$qȍ6d`#HPƱċk>@cf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛<jG5}KIQgzcm%?b0y0jŕR]Cr'6֡7 j 08>rzt6lٳfzj3ƿ7gR!ߣtV@-OIM͛6lٳf͛6lٳfwJ7"LytMUiʭ2~gC1UOߑ/ ~b~n>Cv:0:2w.H!utRyKȯ̘ttW^Q$$jSl^\)鷷O'ה綺д;k[X*WY9&ԴN}?PK1\[J#lU<ɑY~[E][ei4vcg#ԧOVh>iiUvZ}+*4!Ttܓ3f͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳg)|I ?$>c!滴+JONOMbnki+-7nEO&L ٳf͛%=63shIA&M+NSpJT|席~Jb娵 ;Lٳf͛6y[fa[˞͛6lٳf͐Omt#?$Û6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳa?u,j:ij%F@vDÓvO5@wQΡ؈L$;y ~yAlٳg0,ڍǒMFj6dx"@#P~3W:~YdV`P⁘{ <ϡs^6.]p8Vٔٳf͛6ldM"- zvtɍ&#"އ;&lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͐3d]ֲ4nh`y#k88*gD:IC|S4)PUуu+?g;5Ɖqs0/ y@jy x磇A6lٳe=x5Mxv=u?(u&DԄ7>i hJ (csf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳfo9-^ZBZBF@]OpͿȸEt嵸#zIu29ÆFj`{76lٳe8ZT\/m9P=5`P!̶B>|͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛#So}vh,aK)\G Á眓I'_-~Ѵ^9[OnȾ*;g{Lٳf͛)(5>/*YJCr^I93r@+gf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf}'~J,-o-GH=nBQ7e8eݟݬ+qM4rDm[W($R֍Z͛6lٳ0zy3ȾTѼ9x&ǧdjc?wLsyf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳdc6. [SFininJs[y;I}>H-FKPV+lZ6lٳe5J;56+>ӠP6lٳe2R*)\Wɿ}@[ApZx3zfZVΝsf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳa'd򞩡_+HOP!58kB?ޛk5'$M}X$_J uk^7Elٳf͛|BGu/?$~JRhBGu/?ߜgTɆ`qs)Q o?Ÿ'gڔrw8$_vQj9b/=U_'P/b@4]uMWG5%88(ׂOdϕ#"&e=!B7_:ƂcupkdPmp[u?[ȯ=:#X"e6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛!~b\ׯ|.-qfjpGwV d ]^J\7Vaǘ5)-QrNޚD7nd!8~(3f{O'^U}ZL-E*C(l!qCe kq%fH?'b=qӡ]i^Kּt!\i֣U#1`noI Vf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳfCI+|{u|.h=E%G +.k#.G4S\KAk&&c:Ww^*vf͛6l_1t&(z#RMXr[6lٳf͛6lٱ+y%tRVsG2[i5>#KjH+8G7&6o6񬮵A/cC5P!CC ǡ,rĒC#* ͛6lٳf͛6D0U--Qєoqhcg"nQH8#cc3GVCVOo)[j6Ό jٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lJKyGaCVyo*Ⱥ>i MeG/* sf͛6l<_?gO͛6lٳf͛6lٳFٳf͛6lٳg0/?*) wğ ~bDIW 3?9}2/*k//eC5]Ja$Z5+B$@xnBR>w_-Cu4n}EC͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳ~e~ky_򿒵Hiu}e uC Aj֍O9s.@.3y5_i lٳf͛#ZGoRc$s%R6-ψOʙ%͛6lٳf͛6lɣi!tI&`@8R{AA#O۫gKKIv/++*!ևY婤h׷QUXt9vN<ra6lٳf͛6l󟑴6cwuZuWjnyDY$|/+i:y&7YI`^#`@1~]4{p\jWe_B*Aƈj*SSiY夐Dzu4KV쿫ϏO[Ɇlٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6r_/.kyu{{Mk@^Ld 4mS7auȏ[|â*(.8:]O5x";X(={g؀͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6q?yTGîRŨhVu,Qݻ0@,}"hB{q~Win0Ѭ̈ܜ, rӅ)㞣RAaF/6lٳf͛6lٳf͛9?䏞<#\bx(D"Eb()C3ySk>UI[ieẳ<>0ЄGХh75sߕ6WY_]k[{k;{򭶷.%սŽԑA,swOBeE(SOe5oEq7kx.A0A4It(ySR Z鰙Z5iR5wrdz'IЬ4X-յpJ ~ _c/Nm9Z\\XA= ҽ28<^_Z^^$\1k kwX/>B~9>\Hf5e%>Z9a#-oI?}y[a,vuhV[t,W\ߘX,o%=N7M ehBHЪEES^T-qidŅpo$>,O=HgoKקKxn x\I FѕT͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛ L4zQQjӰq/5~k̭B;o#y]+fׯbY? MKx.zt6lٳf͛6lٳf͛8'}eƥ578qXIv*w`?9#̟Z_MIϖ/5KK<Ag] Võʯ< ֱ{o{-{vzٕCzkrhSE%|KM<~VmV/j0]4V!>&:m;g@ޣNZr4p$Wk T+Iँ7隿v'&t pMTs˂|}6̖eoc)2Af<>m:x6lٳf͛6lٳf͛6lٳffvm-QTFz 'z.y:)ou I49ڊY]K sG2n $t'M4}3MK[ T(IV^k s9ߟ8(sQQ^-iGqu]}fwykT#HPw 6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛9G/u=v/%KkXc?NFd3#oVҶb_/4c XePH2cf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛65M?IӮu-J-l,in$4DYy9|jUڈ" ~&,5ɨhR:KlU/'gUyXj,&Yf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳ̺/䏖5X5,m].ZIȖpPM؜!Լ_ټ ]YAÍAXȷBvힰ|]:u;}:+}A+dHDi,ٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͜7sS[x=CQ7x'Vyj$He\IJ{2='Szquon hRŇ6ɶlٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lIt.vULXTIM`ȍ/+M7RmFHkR,** _yyvA-ޟl}Gc#FJf͛6lSyO]75žFi,qս3RAl_Yv$okm K#P$jF&.'fHPE%ۗ,$#.:E$6lƿ1&|6A>SV8٩ۊREQNNk:^jU^i%]Oole4j6^ߙPC >ר:o|0jͦe'../lf?Sճ^RnP? u=SB.uC1im@$/uAp|AiK-^W%Ɨn1V90z$nqGq>hA5*Ղ4hb0_߁img%ŨK?/9M|;'YIRU^Um>y O<۩Ʊ}_JVuv1dFfUeE;;Nlٳf͛6̚v{O5ĕ+jHbI$ 3BAaňZ }k]29ǔ%%Uu&@ rZڍaoXN6WqH䬧3fO9Nλ܋{+q$KN݇'wq]Z^|׶j>6ҵۋ*կf[D`'^*[nGr v*y=&V|um5\xnVl?<ݨk/jW4?~M^T'7Xu.yj1Gu$\fOFxojyN\ooq zq,#?}/=RNt}RK=DJ<}X0iOc=b]VOD)39-R_p2mkmvH$x55lٲ#V=^5+m`C bk_6u_y3O[K$2N˩r`:ϘB1i L}J}T0*)Pr%/>MOlXLݘFHvyՍ6:Z\kau/,LCɣWnu*Οn£^y"/t{U+8K[}3Y7IɎ8` 9;?dgCǼԏO[5ssxvpmv`=6v<ٰ.bo˻C$",~oFZ-_3-]˨) ynPWSB}W_yZj׍.mh)C6'J?GOY~bAkĕoZ/a$RGL#/}GՑcs`/&밮I"jzDHn!vTSkbVA=B>U'žE״XUS) #T`} P|٨Hɵ*g<#u=L!+L:к'dzJhldPw=ɦtٳf4O9f[jzķqD2* 0O䞝0W݅ߢ;ˏk-چIy1Oo^ /H?N:AҧҴ2ZZZX\sHgd(Uޢ|[5-5EL~p((Rޣ)]0';:N7zΫrPv=D~vszhu1wykԷ[x>A?m#7ƿ~PjZVRiZ՞qhcnk ?|yXw|inlE-I7<w D-DҞ9844JO&naA. ͛6lٳf͛6lٳfK).r+ RkE?dܘGB>91/%=u+ԏD.t#8SyXo:זm˺ޙ6ZiZ0}+%hڼ~6 WY뷗S}ZghST2{ ;R~ed[\hII֊E5dKc|>)`+9*mm;tH ֳf95S?5YYyCK4SA&*ɥ⇊~JW}5j:p sC}^?5Bo8~XZX\y@Pۊv?Fuo=J>]_מ`H no $O/,9RxكiMɃt?za换ZyzԚr>m$_sG?ʚo/Oʛti yRuX$sz|o-􅽘=Arig+ w |?"IM_U'kH7ӳf͜rF5_"ǣiV[ҴPHYʃW>|׼iߗSG$GKjj;+RY4G2Hg{S@f@_m>|t sZt0b͵>|U~jVzv>"u/ F~.⡨/\ү|.k+gqoG7Yh/N(1Vfe4/>iijDd*ZnnR4J`=yN3_u[-T^jSZ1$_hF?P{/yH/⺵{kh' GPiDyg˺Vy,mѴI3q*h~* +LKߝ:'5 4;L|ͭ@ i@P8#Sw>OCxyו`E$zL{Oi$E6# #/6lٳf͑}Dҭ.7~^-4RTf/*ʫbʼ~@tZֶl6BԢvӴBWp"59/n.pyJo7/injvAsYJ:6l GI#WZ'e#*OCCMbX)QdWF bPAPc.--.T-1̪jE9qT!ET /^"E}DWӐW2H@ҧ1),gI=RȻ++01|ٳf͛6lٳf͛6lٳf͛6lٳf͛6yvbCkh[үr1HTQ9cb_[I{"e R[H-b5UZ1L)Դ峿J1iwwC zĽGR'5h{|ywC4Ea!w$f;p6lm8AĄ*rcV458h!#JD9 9Qq HQQ@#a$v$wTPH=j@""(TPc>mQu,;tGBH VvRlٳf͛6lٳfQ&֗SOw7m-Ƥ-$g &g~kʵ 4~bS<5X5mC̫kzƆEHpRgj|aUZsAEoNU(oNl.O,hjWL}G4 AQz滥hz{jYc䑂hN%yINsb+9xn v^j$@OB:a}.b.'{;Ki=U7}'q&lٳf͛6lk&"Ǩ_H$dصdrG,k$l7ԂTGPqٱIQHwbRI=Z^Z^[ͤ[ɺMF̤ .mfĕxkQ) xRbw`5[., H UGRVy@$XjVr0,GR1 3asyH]`i}}t4P818Z׈Ǖn/94إ~(L9BȓFJ!PM4GrtnV|Nݮon#ZfT@IjzvKauHu+P$44=0NlF{[r(=95_.èE{opyQgu$da7txӯ5,=Bִsyː=ڭWQ@IJ)=)jfƻ$ڄޒHPgcG!TDk^nCҴIBGǜ4=Ea\^ ˧lVVHh{f0]k6k.9Hfb#7frsu}۝2i-c[m*Ħ0EWZ\>/*y?"^|#Ym.1j6lNwhٹ;lٳT}ٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛9Mi/hy}!dSTݵe"+Oo/y qVxL2Am2!,!d ŃqL.hMXFRUى,ORN~4Uki4ߛ?S__^HuHvhhJfI?ֳ8]i9!X?;3i5픫ֆNj|K9[E#.Sͫx`>y{-"=T,a,gXi>#N*FyZnMմ*+,"KZL\33,^l5nmҔY閭#3.dy$7+ByrWձ:7^T#Kkȥ% P2EP d7>a,t~~1IʆD -80c =A[\\] h"Aű'`ӶHf͞nugou] 3X2F>+r\[:+z[(ˬ[3E$vI$+l'&vh?;.;Jj{C3sC^#+RXdc^ȇVIN>6^r#~`j?ؿ+mRoWͨ^UstNt2@/!I>>eyWvwP$r,F?gly3!uâkwS[ҽDݐ^D5 &&$rYDFp%wɖlٳfo8y\.iUt,8(ԝyV;+8G}j9[g5DBS?0MSU|i ,uc(nhw~Z]IJHJĢ+:|'cL?i6GkpqA;YZbqKK3.\w_cAԞ+Px&ne&6G,)A^&]Vq~0vDP9obw|~/|9-<˽j6m$V@yf(bRvuesSs=H WD>V?WPhE#GKwolU&FuGWhH%ZSGZ^p 3C~e*({t>q-5]Z[˥j1ڪ\J^H92Wګyח#,m직h.4aJ]vkǛF֢h|co+H.AKp* }?4]sEӼwaC]Y\vֶT an5[GIj<c֭"fy,p[Eq$6˽~h;ZE!,.⇐? */"Gzd?ޏu[)i?z4)VI")pyHBdeƯ>_\D]78Cx$herL~b;cԼsi^_"\\h~7L)%Ŀ&pp8Mzs!*Hl{Si>@io~f.5-j4[h בhU#JYۊm$\<^)E˫{Y=K[Y^Q>e9=1$>F"#>:{K!E#V݂IǗg .G}C"^q qM{?57vw0}3ZF̅B\#h% NjS)/L󮃨%_G B$֒T$dFq6Wv^H[ܢɸtaU 8h+O R: +˕*R3f͛6yG4ڢHYcx&T+HYHD"*5{wK >m9ըG$5Kk?0i:DӡB(@M>$$<.[{Yg~!u֭!"!_=:藚wo \iַ:N#K,POg3$JcT:5ET==C#H\(W7z՞#'O}.RIKsa}2Ï;rM'fu}O_ӻk{Ym1k,.#WȺEIj'@ ~J>Lٳf̈́p򽟚<{v:sXI]":S@mqguJв-aęF~ _qyLibMJkl~uB"Yt#k\F'iUPD..ʼY(Vb1cOIgH|ZY/嵐J_u׍Gz!o*nqs30b\.ڴ ,!fcMִ4NբV VoIG +'QݒUifyFHM.&kbX)UZ_4y/aIEmC-وC[N7Pm";+{RK^_zoEIWk:u?Z]iW_+qf}D"GuʋNJLen  (Eijr=0D6@CDE Vniԟ(󗕬˽G.4W1м3B,2;"^1M3chU02 ?`}qyOh؞MNk,~XGA+&X4O8[yYӖhm5\EEo% 1q//l=i6/۝CV +$y%@#y)Gpz(-PR3-xwW|1GiVJ/G{WkU+eٹT8֘3_~c`66M!5ܱF&en6p;]ҵO)[ auw}uo[ 03 xCM_NuE͂pKe,#nG2Y-u^_9Ԏ JX?IӼu}fMm@,hEM!R%ri:\%p=`hТ"6VpI$ROUY/"M9!|_0]^nObL$B*QGlW?,|/ys˞n֯UUWT.cf / '~XBlq%[!&i]+v-Ayf͛ ?5huL:Ds0$hJN^4K9ALn4XeM6v$h#bHSӰY͛6l5ZҼۤm=Ω/lX8Ե%VbQRm^_1h:݇Ԯ>ah{\h}p RiSZb6gF!-O#ŷ%QE:D|jMfMKpfJX/*t8O/{KkMR% 7-)`M jNuy.̗:kVR ' sV_٫uo)_mƓ,޿R;ѝ֠Ӡ_ZAW6lٳfg#:ͧ-h-ܾ4 _A//MSRno෹n6yZ=:[T*/ ffWUV>Qהּ+g#DQD !sڤwX^VG,P?D^_RiQiymarkۛXޠܲۊu4vlٳf͛6l򯞿@韚:׫/s -Zi>?$`` q򎯥j_~fq_:l[hDpT3Թf͛9.^j1I=0paƼ%C8wq>zKnsfMsF'Tu { d1ZIB-s3n84EH[[Ⱦlo5}"S]w@^E"+Ĝ@׏*|.uWȕt%:#RX 0SCsk>~׬Frqjxq#L4v嫦Z }FbMI9!j#$yf͛|9<廍F]Z٣}=o/C k9H&XkɩtRDfԖI8,XU(FFm|tޫCmi112'ՎHZHlٳf歯uOo)hZ?3=`$E$(Nvui'-q]" /=ׂ@ i)N4E)ߝZ歡Y7')$I^FtI<ٳf̀M6H6 "7]Ux$<8eyyG*+=7[z!ǽsYf͛60M}`ZW+͛6lcCH+IDn@%yu\~lٳf͍NȕET;6lٱѴR20H f͛6lٳfG?8 kZ#p~jXUd y|:뚜:k]7Gуx JWn-N3f͛6sO!:5|]3OsFd^;spkmgVIM 1m܊f͛6y@&s X~"a<Z>5YżZ Hրd`ѓrO56q-хB}bJA>ŝё20*EAb-Lu9$m?[@X6JBRjv&$kӸ=3hhw$,MMXjjM%6QHAe>2MR RiZC-SDSQvEYWvl;͛6lQ.JC KT<,NdE47Z.j}eeo1on$$k@}`ѳVk\ge\KtaPX!zwvPzb20!=AMt'm_Z̐8@7`-XOc%]QGF(u8 >>}au>cylNTA"#HAW_*ou4SQ?MkAVgݾ`vüٳf͜ߗ6r~]ythgvm1*#EkҘ[yUcq*eZ*:0XD!A1/EUw?33f͛6t]kE.-o-L Ѷ<8h?z-M{XR QKV}yf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛ |ë\:cK~5ͽ?onGM3kZ_g0jjWwhGɥX[j:i?[ӯ Lvp8+U59ݳf͛6@8*c:oto\ZBBH>z1NfOmv-^GZgf͛6lٳf͛6lٳf͛6lٳf͛6lٳg6ϒ:-b7$ ehW*~x~[y\Do I}5T /&fiO3f͛6l..KJKk5]-KDP8SUziO;h\ٴy`AD.A,~*Wz6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳfȮYmޛ[˚}?@-5X6PXYطbA36lٳg?W7tk "c]wIC:FG98c-Ϟҹ[g*Fy-Q͛6lٳf͛6lٳf͛6lٳf͛6lٳfs:M.6in$=EKXQVi!X4U <ΞS-o]'bXW9BV>{~sf͛6l.JNZZe:/y0l⾣j_v5;_7vMyfC/+ݣ<|_X|~lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͞sEoZ>o/$jVxSΕ~ayJk[ErhXqVFp9гf͛6F#X_yZA Ik'Ԥjl3\s?\ܡ{y"jUy.MO͛6lٳf͛6lٳf͛6lٳf͛6lٳfG榟_LѼզ_X^J՜RBrЃ$bcUP~WyVyu*wpԦ\!cB(Z \9f͛6l'_Wןٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛8e?5+˾^X\V͞;u+:Nuw7,|~:ݶ@,FRvCŸqgE͛6lI$SͶyMSֆ)Q^y$v9è"^ W$h:*ٳf͛6lٳf͛6lٳf͛6lٲ'~^hWZKpY!(raտD?[;żqo^׭TW͛6@?6RJU̳ȺxGlcBŹS_WGHd/k̷s<2;/}Ǚuٳf͛ ɩ]i~^+Kswuek5$QXOE6]ZX{jln游y7ũ[I7ĺ^8%,/OMuΫ_CխT f͛6l'?M͛6lٳf͛6lٳf͛6lRH)O0XPrOFs7x8ji]'7;2Xб R[~Z~p~b~`yhIm7ƒ%ܸyau!Uy֑EiCtRjNryRj5=-͛6lٳ`x$Z@QvTUЮomGo-6J!kzٳf͛ k]Sҧ=ܒWӝ"7,A`V9g\ ^hNh$~Dy5Mi͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lO6KG5KM'Z=HjY FTo@<ՠJQ˞bӴON ˳?"*o(zoN[]f؃Pu&f͛ K=Fu?zWҟXt8LmR?:So^<ٳf͛6lٳf͛6lF5Y]QjzL@s2mZ3G4nƛ졉8?,EK+q ,*I3_GynM^i0X $.5~,_nkkk;N5O*ŽÌ.W򔀿SeKa@:oPti4)՞@N ͛6lٳf!9J3iYMfRQ\Se$B6 ~ZE,^`͵yC G銪-ZwS͛6lٳ̟_^zf͛6lٳf͛6lٳf͛6lٳf(yRYnE- NJA-W#-RdSm094͛6lٳ̟?aT?z=76lٳf͛6lٳfi-vI,0DUQV$]\y[ɐ.QjsFVWXysIAǷJuMSS[ ht[$RYaxȹ|?<ѫӿeTf)jT.;ۍB}bFN %4ߞKkw>S^giinuTFOMXZϚus'+aŽR,l y'A5k?"_Owvu tThG̷2+2ԥ8w(~cr>]tӓEv:JC!bb"£=Yaa+9l`7[gT,͛6lٳgO^kմ(y ?HmfoL5_roaO6@^4MZ; :p*<w~I"ĩ(29+_sŎ^.mԫVRT49ٳf͛6lٳf͛6lٳf͜rb[[t^XB+K,x$gon+o.Z9myՑrz>fgAWcZydZwCzJƌotmBj_-뚉-0j/7,;[{nM#~٩ϿK[6Ij4yX_n 3Cɯ}R)ɏK_4kչH[xsVUe}{Gg(ĭ_ڝ+i~t<;iqNTJpKKID\йa`Я杸FH cRI'9v5{_*4G_Ph0 r;jfп,E[n W׹yp8{5$*`(2?ZjPԢ eK-2?V9nb*RmE󀻰M*ZI!;wrPT! 筳f͛6lٳf͛6lٳf͛6yWyzeѭĶzGaGXpi( nRJ۳Nz@f͛6lٳf͛6~]Nt0XǨiD 3UoȖUƱ FOVye誊(UT$MG|I~;ܭvp PK~p6D7YWͥQ"rh?lמedLw&c5q([ woO-~[i:;.F+K(28dFh\yo$yZ]WOWyYc]6--4d"R;a0_C!mr]yOF $o͛6lٳfĮ`umR* 9=~]:WtgDHSi\ȹYOLBxjŎ.ZIy'F[f,4 :'%1"i-n!A/ĺm:~Wu2I3#G`o|#Z3F[D>~UO3f͛6lٳf͛6lٳf̟͜v +ksy{\X63 KBE(fR Uy̭{m ,4ĚYeI"J|1B흫6lٳf1_ԛDk1ӕ7E:u<8~sٵ yƂiUz6lٳf͛6lٳf͛6lٲF-ǘ4 DK FF5ƃwwgl'QqD@H/8l=+rjaD$w>[XEkn0"Ƃ FDѬng57_S9 y{K_9M]=¾~,lM~0+?JyԄ[Iם"6=P/L.lٳf͛6ko/w01IHu S&3\y\u3ܵx˖6 ˯@ƙ?7K_mu?!ߊH~6lٳf͛6lٳf͛6lٳgп>͚];IimXųEH}dajVO _yR楦e mik16[QD𝑶m^2͛6l9.6Ѭ/VQߕ_N? M|o@[cr(%?>}f͛6lٱH/,紜7UV9H]USxzPZS'G7|.^9eyrHҷ9)rOl?͛6lٳf͛6lٳf͛6l??usLtı4~OA} TrT Ak)uo3ƕy:Πq:*32~'ZJ͛6l]=:SYܛ;YR$YR&ⶕ{~sK7ז6[^bf;V%"+z6lٳf͛6lٳf͛j:Uf%Ƕ]:iX~i}Aw6V/4 -|9{<䮶tood#(1Wa^A8eɵ;I5)6k1LՐGooomv$6HB""*)6lٳf͛6lٳf409]cJQRh7>'8Yo]]]E)I1?zLf͛6lٳf͛6lٲ3_,y9`t[Dy!@B2kzߘˈo*HRaM1H6Du~vM/Quv"'9Y~.4f k޹?(<4G[DṚѡH>$\͛6lj I78+E2 ypѵ%H -#zs6lٳf͛6lٳf͛6lٳf͛6lٳf͛6soο4yCӡԯ:*A!gQV P~Eǝ-chIeM?J8Y#C! _rmW2y_˓XVMcRyON$)PrP*vɎlٳfgO?1=7],7151r(M-#+o$ dFFs8BxW:|yWDt+4헊Fcݎݎf͛6lٳf͛6lٳf͛6l؅e5K=慺2<_/yR?0̚l3#r7 aƼi:Ȗ^L%j_&3w%I(ڬT|=f͛6lm~RhߙzE\YEcqׇ&b(y QZ%8شvBHIOz6lٳf͛6lٳf͛6lٳf͛6lٳf͛6A?7-lm?cvߣu&4xdYsM3Gƃ^׿2-&̏F&ZWeM:(߹@͛6lٳ̟_^zf͛6lٳg2?.uo-yTm3Nt'DLV5g3rWo +ѿ4C?a[4dfD ;=m<+ߏLрvv-UUB@`͛6lٳf͛6lٳf͛6lٳf3ʞ}^fҿ,41i׋%찢daҔi_BYZǗxڄt5nR>/@Cҵ΃6lٳg?)zo6lٳf͛6lٳf͛6lٳf͛6lٳf͛6qP̖>Uo7Ok},# ̜)ܯ]L~Piz&,7@ꑼ̘뿆ٳf͛ ìEh:4m,ZurD *ڧyqg]>w Skr "xڢٳf͛6llݷ𥆫$yo5s%姭(S3kw*yzm}|tj7.i$1RXcqn;6lٳf͛6lٳf͛6lٳf͛6yڭ5:ƃWq\Jt쏯 m^!nVGu?#O$d^c}-ont*Z󵱕C z t 6lٳg?X^g Ѥcnt1)qu=\M4I$&3Ywbi͛6lٳf͛6lٳf͛6lٳf͛6lٳf͐/͟3yKt._iNK$qڳ Nl)=/o?̍;6z|ˢVY&"y YVsf͛6lDu(Qb3󏨉9Z*/`zw6lٳf͛6xrNTƱ4n|i<2zj`Fb5~<+yJ\>Z]E3K+qh Thz4f! ٳf͛6lٳf͛6lٳf͛6lٳ럚ߙ`Լ3Go2Vsi\Ob2ּM͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l/׼kzv|EVKԱ=syNǵ/5%ykA~误"UBHҴ|^t/-N_K^ -p> ]V'&f$H>O0Z5暺syr@L}b7&* 6yqR?O\gf͛6lٳf͛6lٳf͛6lٳf͛6lٳg <yΚkmfX`rLvvV߭v%ZC[:\ C0P(w׳f͛9`i~L g|3hWXo#Hr䕉*.*fy˺W5m /Uyծ};T+M|G: /7\ۏ{Usвs͸׿W7 /7\ۏ{Usвs͸׿W9ߐ|:y{"Ku%$*EwΉB6G^\,sn?uUua_?k^`ҭ|}b)eZ$uP u:/ /7\ۏ{Us~_y+W~qm}g7[.n%0@R?4)6uy}2 [5ii?+ jtԾW(oOJ/kFO6[`^@qYn/ةJ|\r9mG;H'iGKy}8LR$)?H斥Kc47ĜݘQs+2 &]ri>tt-~?<B6G^\,sn?uUB6G^\_o:4k*5?YKH< {A4O}R2q6l44?M?8>3[_Kіky&ɜ;n>T|ϖ:umW̱y\M7H^P~JJsʷJ?OUN0Q|0qo9S#^P=ƣw9$}KX$ys2K*s?(>ʟuMv+5{w*l\潢ZVepX#0CrEѮY|nOQ3\81wy[_~b ՠ,\ ]BF^ WH*=c9mM%nzw#*k|2/.V{R2#S_<<Ğd \}Bwh)*`6w ;(y5B {d}>ux+s\|{oY͟oͳsmҢ~Sw;={z.-?4E L bF4AnK΅*s?(>oV?8IGʷJ?OUN0Q|V?O4/Iϩ1Z.nSjj:dUN0Q|0qk˖_vRl%(-!J`"@iQ_V?8IG5Y[jg|wm6Ծ'&0%yTS~^.5yka#\\76 F ʧ/5U&;S I#0l*ݗ嶽jzL:ݔ[2s} yH`"@iQr:OA% \Ot.= S\嶯mKviKQZK~cVyrsM5sRֵ =?뙦1/ $^C}嗚-wos[}5QB)mmĈT{G\ad*,w*0!M}q83G 1GȠiimpƑEP|a0,(!nOS#^g?/Qtqu7=9I"k'ٍOĀ2U6lN[ki]^XGO̠bzb7EHO젰=1LN[ki]^XGO̠bzb6Ж0đ݊(Ze$y;(,;OL'1!tWW$wO̠bzfK[dwtnj#Koa#:ydˉ=)>lٳb7VwsY^—(O2:8+))q8{M.7bN=/?;6i>mvi"Q/6lмh槭=ɿ_RigyWx#c]m]o<:ed5CM!\c sf͛6lٳf͛6l.ߗ+}RLԭ)[a拉$`YhMv8c6lٳf͛6lٳ`]OJ5[7!KkYcn&B+Ⲱ(Ƌ֊)y̚eK.T-╌.E+PN/t(h]󟖼T5}QiK-),1x흋6lٳf͑V-SʖQ_i\Mq6Yz|6}4>lٳf͛6lٳfڕz},hiejvT@I8W8io򵟙4HФV@Ղ+ %RѶaoOpd1+q^U(>f͛6lٳf͛6F|/ImuqF MEdFYAS_l1G-hڛ6H5,J"$w` yn/˥kۥڻb&dn.8؃2lgo+#Ֆ0ixN3f̈́^x-]k: yM`4BQ!*P3"y/O f͛6lٳf͛6F?hO_,\Grږ%-F3+򙸥BS 7/h.VKFul n(P*N'yKF_n,䧪YJ#pKҘ\i*,r,1?UT^1ӶA9!'<1ISC,!e!6>`m|}nT^A\Aw7Q*ƞ׵+hZߦ{{EsxȟCd{C|Z=VJ>%"xSv; {f͛6lٲ%yNͩ[Eg51 |\7.@=r[6lٳf͛6lٱ .'y)T)=+$/|o奾mJӚ$"? ]e~? |N{t{>;]MBY|cx/h'Sc^?͛6lٳf͛6l`O8iv'Rm>;/$[WERy7j򍗙'T\A} ,7P0x7;`}U eկN=Cs,CjKbN8Ϡ ./N/kNm(h-aƽq:3f͑;톙l:6kxUi ##c~rߚ_(^1/Ut,K1o}y`pl若y"JPȤk,ٳf͛"S-1kjiw$+Qo$sN~C%f͛6lٳf͛ |ۢ\k[tXnܘb̅rAʍNʚ6CL^lh"H8MX@W4*CxoF($3zfE]#Sٳf͛6lٳfȇ}˺zZ{[SoZ?JOQD4ӈmtUW[֗~$Φ9c2WRF!yN}zVq^f5AoGm`2E9I$+ӿ*Q:~>yZe, B-ԡtj%wjٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l'_,ˣu4&sż4N:2rO)~\LjơƋ>pa˙ɡv"~m$חeu rJTvPl陳f͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛"z晪6kpZji)D1y04،6<0$m' 3>$? 6͛6'qqom6yf*f4c}kg夂[i<2@e=Tl_6lߙF-N-/NA"XTڜy2oJݵ7v #Y`wWeaA+n]: v珨W*tN ͛6lٳf͛6lWmXn4-VFQ5 >hYyWcnQOCVP}y#U򖧧Oeiv'OhS$Yf͛6lٳf͛6l50鿛ߗhV*k|ג$<A}`iWiw=95F&U BIQ^,qWsf$q{yno t؈n4Hһݘ|:7Mk]%PfHdWX$ VlĀ*M8盿>(lEI$m?'!ZM=dtu.eOP7 ׏^ $9|e}ndУuT%s>8CUhXI9*##6lٳf͛6lٳf͛6lٳf͛6l_̟k% >7_&Fy7^qs`a[kA@>da׺5kigV.ydYBj<9<-:W-$Xhbl%z(in|+A,tm\ BZ5!c`R=v7Pon9¿ u7k4?-\z>`<=?ɭ~i~Bκ-h.^,3I**++-)O:E-Ak{:sLrw6lٳf͛6lٳb6Vf!72(RNBlٳf͛6lٳf͛6l'|0+~zo/~RZ>T.+zy.D s;ps~Ry_>[ih4+ˑ{0ܵ٤H$N1֜@ۭ2'sqs9C{O_\[? `O.v'V-J4n[5PT-+AZ\s2(`mWڛ7sJKC= ,a/;[Mљf ,RiZ.ZNk;!t:ZVchѼqaZ:-#hh$f#~KVGEB:7Wϱ.neI%dWp"ar㩡r[?'j:?Fg;V/4E%wiIe0qQ?%58d]&8&x@Ε6lٳf͛6lٳf͛6lٳf͛6l¼]~v6v&FX[9%FdUauJ/=kv&f4qeycص)ZxoW:%|no<:my<.,s"~xcNj6RӼ4?2ZL~qgyHw{]TfyoZŖWfYI}~| .,iR^b4;{-MA rx#Ey8FaNk_I+|qcZ3LŌ(O"RUkSҙ?=?/8~\<r4ZCqEnj2~MvмkXN͚CܔHFDU  |_3ך^3y[+}=4KlT>sC}%&F~9*?2t&g :y|GWQqYGmǕw޵ɷ䇒nehwV&s+'\~f͛6lٳf͛6lٳf͛6lٳf͛6lٳg<$<g/qnSvǮwu KAF#1FMC lekO/>xۘ!UyN0?-o4yfC5-h&5kmd.fs;a|'Ԭ/oIu yyA',(IN:ϗţq'PB4$N++F _EhVZ_A:!J UmP,lԣVo+dވK~m꿖uYԯutrliGutyҌgju*oOϗ4NYi%%Ƥlٳf͛6lٳf͛6lٳf͛6lٳf͛6lXMğg_{a??y?=0</kwv?տUλ>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 59.7543 177.8456 Tm 0 0 0 rg .0189 Tc 0 Tw [(p)-5.2(r).6(es)-5(enc)-6.4(e)-634.2(of)-638.8(no)-5.2(npa)-6.4(ren)-5.2(c)-.6(hy)-5.2(mal)-633.2(c)-6.4(ell)-5.4(s).7(,)-635.4(h)-5.2(epat)-5.4(ocy)-5.2(t).4(e)-634.2(n)-5.2(ucl)-5.4(e)-.6(i,)]TJ 0 -1.1116 TD .0186 Tc [(c)-6.7(y).2(to)-5.5(pla)-6.7(s).4(m)-352.3(c)-.9(on)-5.5(ten)-5.5(t).1(s,)-353.4(and)-351.1(g)-5.5(ap)-351.1(jun)-5.5(c)-.9(ti)-5.7(ons)-5.3(.)-347.7(A)-.6(S)-5.4(O)-.6(s)-350.9(c)-.9(a)-6.7(n)-345.4(b)-5.5(e)-346.5(o)-5.5(b).2(-)]TJ T* .0207 Tc [(served)-487.2(as)-487.1(traveling)-487.2(t)2.2(hrough)-487.2(the)-488.4(cell)-487.4(t)2.2(o)-487.2(c)1.2(e)-4.6(l)2.2(l)-487.4(b)2.3(oundaries)]TJ T* .0185 Tc [(t)-5.8(h).1(ro)-5.6(ugh)-627.7(th)-5.6(e)-623.1(m)-1.1(e)-6.8(m)-1.1(br)-5.6(ane)-6.8(,)-624.3(and)-627.7(b).1(y)-627.7(7).1(2)-172.7(h).1(,)-624.3(A)-.7(S)-5.5(O)-622.8(u)-5.6(p).1(ta)-6.8(ke)-628.8(is)]TJ 0 -1.1174 TD .0189 Tc [(c)-6.4(o).5(mp)-5.2(let)-5.4(e)-.6(.)-491.4(N)-.3(o)-5.2(npa)-6.4(ren)-5.2(c)-.6(hy)-5.2(mal)-494.9(cel)-5.4(l)-494.9(A)-.3(SO)-495.7(up)-5.2(tak)-5.2(e)-490.2(w)-6.1(a)-.6(s)-494.6(s).7(at)-5.4(u-)]TJ 0 -1.1116 TD [(r)-5.1(a)-.5(te)-6.3(d)-258.6(f).7(or)-264.3(bot)-5.3(h)-258.6(W)-1.6(T/WT)-259.8(a)-6.3(n).6(d)-258.6(H)-.2(O)-6(/).5(HO)-259.4(a)-6.3(s)-258.4(rev)-5.1(eal)-5.3(ed)-258.6(by)-258.6(a)-259.7(m)-.6(u)-5.1(c)-.5(h)]TJ T* .0186 Tc [(d)-5.5(a)-.9(rk)-5.5(er)-287.7(st)-5.7(ain)-5.5(i).1(ng)-287.8(pa)-6.7(tte)-6.7(rn;)-287.9(h).2(o)-5.5(w)-.6(ev)-5.5(er,)-290.1(non)-5.5(par)-5.5(e)-.9(nc)-6.7(hyma)-6.7(l)-282.1(u)-5.5(p).2(ta)-6.7(ke)]TJ 0 -1.1174 TD .0189 Tc [(f)-5.2(o).5(r)-454.5(H)-6.1(O/H)-6.1(O)-455.4(was)-454.3(n)-5.2(ot)-454.6(as)-460.1(pro)-5.2(f).6(ou)-5.2(nd)-454.5(a)-6.4(s)-454.3(WT/W)-7.5(T)-455.7(t).4(yp)-5.2(e.)-456.8(The)]TJ 0 -1.1116 TD .0186 Tc [(m)-6.8(a)-.9(jo)-5.5(rit)-5.7(y)-397.2(o)-5.5(f)-397.2(A)-6.4(S).4(O)-403.8(d).2(i)-5.7(s).4(tr)-5.5(ibu)-5.5(t).1(ed)-403(to)-403(t)-5.7(h).2(e)-404.1(c)-.9(yt)-5.7(opl)-5.7(asm)-404.2(i).1(n)-403(a)-404.1(cla)-6.7(s).4(-)]TJ T* [(s)-5.2(i).2(ca)-6.6(l)-426(dos)-5.2(e-)-5.4(depe)-6.6(nde)-6.6(nt)-426(up)-5.4(tak)-5.4(e)-.8(.)-428.2(B)-.7(y)-425.9(qua)-6.6(lit)-5.6(ati)-5.6(v).3(e)-427.1(a)-.8(s)-5.2(s).5(es)-5.2(sme)-6.6(n).3(t,)]TJ 0 -1.1174 TD .0224 Tc [(gr)4.1(eat)3.9(e)2.9(r)-399.1(A)3.2(S)4.2(O)-394.3(di)3.9(s)4.2(t)-1.9(r)4.1(i)-1.9(b)4(u)4(t)-1.9(i)3.9(o)4(n)-393.4(w)-2.6(as)-393.2(ob)4(s)4.2(e)-2.9(r)4.1(v)4(ed)-393.4(f)4.1(o)-1.7(r)-393.4(HO/HO)-394.3(t)3.9(y)-1.7(p)4(e)]TJ 0 -1.1116 TD .0242 Tc [(\(F)6(ig)5.8(.)-324.8(4)5.8(\).)]TJ /F10 1 Tf 8.9663 0 0 8.9663 310.8472 178.5259 Tm 0 Tc [(Total)-331.1(plasma)-333.8(protein)-336.4(binding)-332.2(and)-335.7(protein)]TJ 0 -1.2266 TD [(binding)-332.2(proling)]TJ /F3 1 Tf 9.843 0 0 9.843 320.8251 144.9638 Tm [(Ultraltration)-468.4(combined)-467.5(with)-466.3(ECL-ELISA)-465.6(was)-471.7(used)-466.1(to)]TJ -1.0137 -1.1116 TD [(determine)-245.3(the)-235(exten)-8(t)-237.4(o)0(f)-238.3(plasma)-240.5(protein)-245.2(binding)]TJ /F7 1 Tf 18.9667 0 TD [(in)-238.5(vitro)]TJ /F3 1 Tf 3.1563 0 TD (using)Tj -22.123 -1.1116 TD [(age-)-363.8(and)-361.6(gender-matched)-368.1(samples.)-365.8(The)-362.8(standard)-362.4(curve)-364.9(and)]TJ 0 -1.1174 TD [(QC)-297.8(samples)-299(were)-295.6(well)-300.4(within)]TJ /F8 1 Tf 12.3315 0 TD ()Tj /F3 1 Tf .5529 0 TD [(20%)-298.1(of)-295.9(nominal)-298.4(values.)-300.3(Re-)]TJ -12.8845 -1.1116 TD [(covery)-319.9(was)-327.7(98.6%)]TJ /F8 1 Tf 7.6719 0 TD ()Tj /F3 1 Tf .72 0 TD [(0.08%)-319.9(\()]TJ /F7 1 Tf 3.237 0 TD (n)Tj /F8 1 Tf .6681 0 TD (=)Tj /F3 1 Tf .72 0 TD [(3\))-319(calculated)-328.2(as)-320(the)-327.1(ultral-)]TJ -13.0169 -1.1116 TD [(trate)-618.6(concentration)-618.3(\(ng/mL\))-615(divided)-613.9(by)-618.5(the)-615.1(initial)-614.3(total)]TJ 0 -1.1174 TD [(concentration)-722(\(ng/mL\))]TJ /F8 1 Tf 9.6936 0 TD ()Tj /F3 1 Tf .72 0 TD [(100%,)-717.4(whereby)-719.3(the)-713(ultraltrate)]TJ -10.4135 -1.1116 TD [(concentration)-226.7(refers)-227.5(to)-227(the)-223.5(ltered)-229(sample)-229(and)-223.3(the)-223.5(initial)-228.4(total)]TJ T* [(concentration)-445.6(refers)-446.4(to)-445.8(the)-442.3(initial)-447.3(total)-444.8(concentration.)-449(The)]TJ ET q 420.92 0 0 489.883 94.507 242.362 cm /Im2 Do Q BT /F5 1 Tf 9.845 0 0 9.845 59.7543 225.581 Tm [(FIG.)-359.8(2.)]TJ /F3 1 Tf 4.1404 0 TD [(PD)-353.9(effect)-360.9(of)-353.3(ION-353382)-357(in)-359.2(liver,)-355.4(heart,)-356.4(kidney,)-356.2(quadriceps,)-356.5(jejunum,)-358.5(and)-355.4(lung)-355.4(across)-359.2(dose)-356.2(groups)-357(comparing)]TJ -4.1404 -1.0077 TD [(SRB1)-437.7(expression)-432.4(as)-434.9(a)-434.1(percentage)-436.3(of)-428.1(the)-436.2(control)-434.6(\(saline)-429.8(dosed\))-438.8(group)-431.1(in)-428.3(both)-436(WT/WT)-432.2(and)-436(HO/HO)-434.5(mice)-433.8(at)-429.5(72)-169(h.)-430.5(PD,)]TJ 0 -1.0135 TD [(pharmacodynamic;)-341.1(SRB1,)-331.6(scavenger)-341.7(receptor)-334.1(class)-335.4(B)-336(type)-333.5(I.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(PK/PD)-340.1(OF)-331.2(ION-353382,)-332.4(A)-337.9(MODEL)-333.5(ASO:)-334.7(IN)-335.1(WT)-335.9(AND)-330.9(DKO)-337.5(MICE)-23255.2(229)]TJ ET endstream endobj 113 0 obj <>stream AdobedC       m s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjz?NlٳfZ޷zM֯%eʢ$5)=2 -$+Eo9C"!XkL:aq_ΖVh 2έ\Lu/Mmu9!"1EN΅o<Gq,*C+# )A͛)]UXaclߗu)+u*M_vH0P8!ڴ鞤`h`74?/<.Ϻu_ nedⲷc |6>H_OTF $ /VDo ͭGI<.os[[o-,vހK'7ژ}O7kƝoiI| Љ)maiDRs>&\_fi(fSfHŤbIVVhkMxZy-.ei%IS zdځ˿w@`46 ,a\O*}j>>G!cY'v550ȷ5cu]EZ:HGJ^${;l|ǦZ'FU~x/F_=WԞdrlԭ;35;?$H"[@u*q?d KyoǮyCWaZ9 8ug:Et6lؕմ7Vo:AFyqQյ7Xjse/jxшM,go5;m#^^{Y.4Լxq.gzOxt-ܶqq7OHj)qo2[[a^0EgcyO'~jQn$:=KM!" TMj-L ѝfX,k"7ڴS|rS1y˚;tXԅw(cTi,ʻtg hgE& *2B1\ٳf¯0^[KSN)nX=+ySO "iR(٥0T_*I_Z6#:"Ny_1y}.;E)ݧHSyv˾_VqOJ>α6l_-󚚹,@Av=/=i^hKƯzQڇqLBPWubkKǞ FKp䮍]'>d'oH:kC`z/]ާ MKm7U80߁CMX<+X-vMz;^zGx4D=2hWgm忓ci0hf_F/9|͛yQV|򟚬vFAT MF@f"FO/ֿ3&hNoe˂c`: Ώ/&7]Fh%InVHׄz{a8%F1kvA&Z5'?Voteiۛhb䃖;MM3r{Wm@M{A,]er<7UfZm'Ui7Ƭ G?2u;-l[y}Y?dqI&-V% amiw-~7Ns;{[%; %hY۳f͛<_.ϖݔwBrĎX^q+h?]ӴdFa @g?'|Kyyr]ud tw•Zu1mz>AдuXuKֹ3[XZF%fUBS;r()'pxh Zlhc?-Tym"Cx`1΋*幜`G}+?V-m!Sqkor(:(PzN)#46j PAf͛6ys9~Qsv򦛢YiZ4zڀx4|(FSPYn-cY@Zsye]Gw(ZAcxe"'u;/s6kޗ%VO+{u B?]Dk_V =r+Ǎ+McEӭ.rjVN kg'qQFvW(Ier?4vC~NyJ졑R Rl**-Ii%DYBK4*>SLE[@N5?_\ݢ*$"D2})MD.rƏ!yI&q2*,khuADJqVq= 'zuԬh~;;9&N5@jF ͗Z?:ǙM?F[qtcFbx6>/$IOI Q#Zdki(gF@ WN oȼ}w!ZazЬGk-óveSGx_o%O6[I"B.cP׽#w}䋽B,l+m8ĢF>֘i^ŧivgc6 "f͑O˻丸Η,ye{8 36+8#I/{{:}₫smmRmt#ZTK!zfq$O> t.>kKlE,D|iL?+\sLKi.T $B(QlTYtEťV6ݘ%T|5` -H5V"5_H ^R]=8vThV[%m#졥v.f/+j}k$ōEุF0Hڠ߾H3an.ki -  ؕŸU*?ыkNl-4ONYtge4a8Z5ɦ0c`5W*,в}~. -\_R; [-BdK9dC<.㗬M7M~K .4~2qsu CGA2#QN"E`:yȾX&Z-Iy©cV1,NH!yKeƕuX4 _9EkǾѥ&岴uNyd5R;D88{S$f͛6lٲ3yOҵRǀ~iRxkkLQhjEEjt4m E+I6޻m3b/knVĪTr0ʾMu=NY>s ]E~ (ZD -O$͛^p8Ԋ wItM~oCSSVZ \e_ΤuK/ͩ}y?5-Σ.<9mt+=JkE-APt^G+qMo>I!Wa6XQ@8ҁ~˶-umb/BkT'>ݲ y/גz5u:kdd}qKsGo,m']~T;alٳf?97e,Z-ݵƗ4"]UtPlȯ3M8{xb\pS{ Nmf[) jS Z{9g"|o.]̳[ykREr=cWr|~]yV_+y3Knf.[չgw#4jdtyC͟򺏝} OJo[rSh[\(VhmRK%@!m Cws,[\ =VL|[eaw0'?(5?GV:^ڂG o V;ho#A$Gq[̟vz͵a g<67QUaZߏ)H_ihZ퇟4o6Al49_˨E%$}1G4dVm\i~h^CiZ"0<$lRym=6R@`&~WG{ ~S5̇:=ĊHnTRe {{SF TDTq-o2Gwߛ[eizմp4\PDl:/]NI`|\\қym/$$GJЩ\#9/ VɧZ[x,G I#N@2k6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͈]ik-܌PgHD }*C7c&GIRK-)?gl.nE%宕J>3M<򿦐GKOBiC}7\vHo4}BxOCu2t8m6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛9gӇ䲝Ly]/D\yS hw~K2\_~Y\G'd+KQGB5aIPI/+Է:|-}2Y m93wS/.'|rS]ZZ/Oi4vvې57'Z/A߬cǥu-+&Oؤb͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳfk{/sQ?5bj:0<ե%_6ETo֌KkyU|;/ˋި-Zm=_ȿ5E:{݁Y]b-铝GOwt]G3v=Ep&;m#Qm.X=yq> jۓzO%B*+C#XF,в@aGX&|/5iv]w{=>2KJ1ݏQ bt}"Ut-5#nYRNدaMhiR:qK : #?:HθsOr$еm>S!':lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٲ!̍Am`Z67s=r+HʫLj^8;^j_2"0[j7v6KPco!1w{9jW`'P[׏%R=#[kE.=Q[\G) aP:ʲ!{[;Mr_+wck{)v7Q2)TZYb$t^72"5mN8韚柔#Ⱥ7ZYKKJŷ͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳg2 ~HGJ:տFJ}8޵ΛZ'L^V^a'秜Uu6GoP$G7J1mQ?Κ}C\!u{GC%r(=9T5ƀd?kq[O_KZgRKi֯/ԇc4,f>o>S!':lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٲ)^.~gz7rnJѳP˘^3ɾVO-Fnc=4.2,AF4aQ^{'to*'HҽoEV+J^IM=AgNzf$vING6Bֿ/|_]^]G26pj+QWKSc;m8(($h(U@c_?<=[6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳ`oLԴ.4XMHJ?q;͖7RjCArַ %@>H܃瑹i/󁿻a0_FwZ\_֗ƑԮ=3"J!dmUm?姕ǖl.M*$68sf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͜Zm[ۭ7GI}K+?KiH596aOKRyRPymnt f `El(n/ϭh5h̲oNbtϛ,0/!z7p>YײŸY,Tl t(/{m[P/6X[(2a^UVKGdpC*L>$iџ[֩$W}FkU)ʀҵ=染W^\Y f.>4.\lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͌aL+$9*~sYǣjz橤ϥiV3Zy.KukvR(1ytDHgEFf3D tyeٛ[&Ӵ]eOjkכ^GKԦe{K; VFw D<| ,~k~vGO]wsg?%ƺʽ$?GZS)=~7I)6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lſ!`yK]| yO ޽o䶒ZkV mo4([x6Ou# *| kʚlNȻIuy9,DySNtVVIu/W^>%5Z<ޛF'tH:rVoQcu44{ĕV6s>a4rT{(Vbf0~5nCjF l,.of ZDʨ99XԱ/RԴMJ؟^<@v4lk5 !"fߌĖ25?W6lٳf͛6lٳf͛6lٳf͛6lٳf͛6f$) TO06[y?ѸK9NȞk׶{#Iy0HȘ0vҧ%o7tMSL/2[\**plp^݇':X" ~'@ƙ%% '@}(UPaq?BJLO`l9K+YnX-^R抣yo+BA4,6RD@^Zq=R+lTNr%W|/_mn/;6^_Vd4 1;3(x؂R*;_MEq`B$Ti + 6iEg֡W ͛6lٳf͛6lٳf͛6lٳf͛6lٳf͞_.q Z\>n󥬚}OkeIYGEeS<ME~-!p$g0·f;m=ZqAOcFn+?؜_yVyN~,y!Hgܖ~xN|yBu&Kao&HʬZp[KenHyEWAz|ky-e[s-,iYC?`R)@FӉ6 ,瓡˧\MkI{A ԟ\91z~EVB)ɢ/IGHr$r\QunO_ק)ͯ`J1\}F3Lv9mOM]{ɼ,V-WEzSj~XxյM[C[-{DxEp*F <'%l>8sd_N"6ꚅŲ Z4GNDM{.Imr.aIߝʲ/Yz~0ʓz5ţ!~#޴ELH;7wy&=/4Gk]:va-ƔPKp3q+ƻ1ԵO2_WƟn&e, O?P:~h1nc}q-oǘ0OQ.6>F-o3~t,ws5ݴzS,DlfFJz''MgO4-5g$:D-;zwhyqWuË(<_k=j] ٽOZ)5#,*oZm]5W{JrMhGĒ?H;+=VR[ck@S$kGUe=w6lٳf͛6lٳf͛6lٳf͛6lٳg,ּ~ִ߻o(kֺ]G־gk+8&1cE'y]i13YIq4*b^\nQlXS=v:tskh3{%fԯZG/6f:nao.ywͿs4k۽54fB?ݎƞ8sr#͗Q[MNaגF?%'ͣκ:M$jhi=8g?gA͛6lٲCʺ-_00iW-/*ďS6͛6lٳf͛6lٳf͛)]U0B>ypJfuZr TTҤYA Hf͛6lٳf͞fi/'#:MZྛ 2B!iSNUFumMX-ZmcI$6]H#F$9tC +$l*PFW6uƙkZA].l08^+?.ip0 IFVU0~QNyGun=/^AVꞭڜqrY;FJV%;Y2AJyf_M9LHSa/Z6tG+n-=^R?Lט[}^oHRJ3r٫y{qɿ7>cO0,}STLlkmAׄJE?8_7,"s&hݥ@ѲN%O~Kwy'̶ZtY![V'աDBiN[ܜٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf̈́^c{.H羖CreGm rE7&U SH 5XXմ.5,: *UP`A<a=Ay9OTLDO?* 4O/iZ,3GaVw<4dW,nv8Ik%&|0CN6t~{ߓݩyjBME%RDEz+y9Q;y6%Ơd q,2/Hj}S:<ŢywJV#Ӡ*%]i^i_ߓ_6X7Ӓ.y@.{2%$,7)$Hi$`,ƀ$?^g?-W15Gq*XcӵS6}o|" JmIBˁjV36lٳf͛!:$^^y&bG[[VD+Z%s̿0?_A"_ԗ/Ԍb as F!|+žex[B>$svf|=]:'nම0+NU%Ҙ2h/<7&ɌmX^^9ߕXmo(Xf-;hR6ݓԡuj7׶sLѴhL{yX?GЛ8ĊIAbd[\е4cv: mfD*9-v<9Wo(Qu{]J 5]Im q)b#*"2.6UvYX^g<,]yZkvm~nd ܸ׭9 w)b3Gk0QV⵩>ysǖ u zwFdas_8/q%M\u1T|Ie"?q;lٳf͛6lٳf͛6lٳf͛6l?=*G딓z8sZz*ko'F=q[zY4;Yf8sɑo`ٳf͛!_Z!]&7&ST22dPC n ڿƛO.i>r4;IĖ.\0rn +'"Rg[Fhlc9.EAIDN@7D<﨏dji&&f HxA~V=[6=No6Wv:d-ۺBV+a/;*i{N=*˪i~3q[n\:ϕ6k>[!^/8{{ rٕa8Ik%&|0CN6tZ֦uM5{19覲n7qA?QoTmO/U?^|Ξ[%:}эz֍Cs:-$?/b[pe{OXN?=?"h^G^_Q$7EUe*">{~~[2otHJZmLƱ-?oT/ZP)?RQ>u=f͛6lٳf)7!tnlٳf͑?y|a75X> dHȑM #9k^lҒ4DY(dKukXu9ỷza$DQ6VF86!B ;S4vvIsLޝ904ųf͑moSBԥ1Xjq3Z2C-Tҿ7?,mF7M6wtޝS+;ފSٳf͜?_M>CNwY5g M`Ui>|G~kF^iqZ̐A SzIRdJzo&I#6F  ;sXi̟e2=zʹ|XI5Ǧ+}M}/v4:؏mWJ^dH"1SGM&Νs5ֳFs}C)[d˷\~;[$GI!22u/LE_iӘ*n&<_[˯%_kcu"bQFzo[f63%ë#ny64v]Ҽ{CPY7 Ȉ%J"l+h.H(~}!iO{D@a0Vl[OeZdO.L{ⱳ@/j#S@84RPu=ɴ9qsOMpxJԡ0ͺDzsڎ"O.U5yVm 7/>XWNr7B+$9̼ۿ变.J6 (uoc<|jwg3\CxPBw˩)ѪAo5V'RMj6pεIy@tEM6cVQF`C|G|y+慣O;3H5 Z2*x?4u+he+ueYTF::&|͟տNA?Ï8}|*t$iY?--t{1]j0Mr" TGŐzGwl|·UKd7.hn_5󮽡ہ`OA)c>kd}wTO8GBo!.nį(XŸ UOd?ߤ,K,^Gir\cRD=oT+Z鎗2o&DE(9 ?N׼y6pG!2s$~AeڶGgnM'E#$/kG/g%잣Zh#N'&~YТt[fbZBHE|+g\Y_up!/x Qҵ~gEɮhpsZ?Nm Il6N*y7q,yI1;[qFsWb]dX6TY#qFFN08n$T eEac̷Q[ TQ#ӓSy{xWEgU~_6yKr'ճgs^uE9u{ x,@Ξk˫ c5 jB|2E5XkOդrf 8?7y[@zi=7nXn$"+BFs?7yW@a5{M0]OV/SMˇ#9 3_s?Ju!ݕBH#=i6lٳf͛6lٳf͛6lٳf͛6lٲ쟑*[矔zl^lٳf͛ZFH..MeTv yp揫#y͵j3csˈBޝ+y?rkF_M/?Zخzc*y{\xUHU9%qFY O{}hW蛻8x-P#Q pxqx헤hVlmDƥGO#,{pnq?BJLO`l[*O Ǜt<J.(2!~Ol?'tagRoԢk^*{<ӡy;ϚlIk-O?0H}8ʱv8Yuss$O,-ȶC芥y}<߯Xy7Rn4nKE%oDACYG{˿ \0͛6lٳf͛~yjx( haE Du$9yw17ާUϱᶽia.m1nZ}Ҧ}.yO)%7vVd6lk_o?gϝL}M[&?WE(?cHqև˿&7kttϋ];J7ﮬrnTSvϣf͜rj|EE*'dY!ApJ/(y F4(ofVU98kWP᲼.l.6ba )8tO;WRjCs$MjoEZ~K/P_aMw$v&zDS[bn=͛8ǝm.ͷL㹸7K3;K,orG^u(vvY_xy h&H;fU4o?k:laBT|cYH>?Ze{jg砦LFJX+X/mKKdЭc%mU"%vU4Í3ڽQ/mOݒG򏒲~%ɞq?BJLO`l[*O 󇓴=,iOcd'w5̊dHXUH؁_7џ==ɼNysR_iqg(0ɵ ٳſ],>bmOR; {[qJQiΧ8ͫF>gj{^sG" s͛6l֫owC⿛.sf~xny+T{MqyfVlGXv~WBq5Y;}t -.hȘF sfȯK/5&L6x˷1.C}5އ%_/նE'Ʒ PcBQc.m#QEC`{6rLOo5 "8ꬬt=+WK+^\P! *"1; <͛9I2oQQgO)yU{[M>b[<m0^L^4>9Imq ֿ/.[yݽzbVQdژ9~sygZ|kmvFm<,b\T9^|YWsKİjʤ[Ҁx}Lmu=6QnvqnLru4=68'6q_o2ɢj>[̶U[œT}8jWV~;/0bZu(fRX9a,Lb.*z3guk t<Զ?u̿X0tխ%)E?8w[qiK֩]Xe:/oM~Fy{S,ڜ-ky78Ky)hoL)#i?0hޅh.6ӘI"9̿}kɚ^usuwR=BpTg3¾p֎?ɱ ~b#{_qsџ%Dɝ/<ŬhP=g6lٳf͛6lٳf͛6l ߛϗ-" |{=ziZ~gNVY>^Tx|8pG?FƗ{gjthy}Z{dNWyijKmjiBG,%)Z X"9de;d?dGReԼ۫F{GN4R>\YЮl.mNf{ ,eaMWKsg.#Om*,?Mj_ʲH?$I|'L6L9I6vXY.Y1i1"63[@]/L\ݥ+#Pfe`Q;^lٳawt-3]tN& Ȩ̎;FBXy[S~U%R5YwY +)TE2 {N1΁گea,:&}u}*K(s?%du0jѸUΤ_^ 힆}3?q99m[Q?<3ϾGOMml:UV7џ=;o*MŞgA& 3g?>"|?:yk@-.q$+,+2E \ߛ~iyIK 3F@IRrM?}˺~k=k%&(P*0/'&_5Yj:zj!&ɚOlFũa{/WqI,sF_=kM.ʚ&yN<+ԑpMSX7'哼ٳß䶯,,Q܅Q[4潲GmxU\_Vx'E3$t!-w5gF XsG >)R;7#Sr~p[ɰiW46wSwj69=:V[ZOē$D#6E5Yy7a_\κo|0YIġXWڀz.-OyTeֿĚ^ VCY)_^u5k5|o woVgUdndOs=icO}>@ +n,C{6rɯ>eR0]%ipuqW^]׼樵.S txR$#%CBFm?(<6h‹n%U+$R KwxlI,=Cf(JUO=ORymCSPRJ71_ߵ\1KkX x#U1\˿'?H[owW:k:7 ~JrBwSN4[ZŊAj%iV0X!"A^ Vaჳ_䝗W8g?dsr$1Vxg|(&u'oXs8[FlysO8^U7z[˿ \0͞4ւNɜz^fu[e_2oL<>neͶ%~>&'MW:|wwiQʞ[L"6GK"O4dX~Q?.ܥ_^(npU_|6xGHWݣg96WnY*E۟'0GGд>i"Y;ӑŏJ ߘg-;O{]iH58)!1>0^sO+=}cR$gnLy1{8C,3dW_%y&B:5?.>TQ1Mn6x+Ξ4͜gGˋc^:G'^KWQHE $O6z7ye[9 %$C%V,jkA_l|&]WJү([9LbZtƝ뒽oWѴ{Z4$97n#lhyc{ZZKgm7c7?m=w&MdoQo-n?&Ly-g[GK^9<ٳf͛6lٳ`}F,l.o]KO3" _WBtW"PGV_F:` ~%hon-a7okÅoٹH\ZVYn+Y#+Anbjěf͜ߗlm/݉.~Pzn *i_Υ9?:~N|vu'ؒ/yOy|L)/͛6r>dV i>bo(i_Qx}ǍpzֻOw4:cn:HIڃ澛m'zry~;TaO:m'MX:XBU()˟''šYXGv~yJF|/4~X~MBj jj:lٲ9_[Ѵ-^TEއ11@#*Y{}?ʋ9Tvq[&Y)g$?"/0q959Zfp]vBcP8z $=o%|àh>yiM ZH?RKmKY3f͑/o)kZksDi>f&7ZM82dmug6]k/G5&t5H*yHQd;v`: <٣iE%3z=jn/xIZޙqG˞tth }sk lGtǖV=Px#>kQY]瑿'?#4XËSRԕőKbamM>8-U#'6IV7џ=;o&MŞgA& 3g'?tc=Gataɝ?Sz6l֫kL^_Թ'96\_1#c9 edɆ~TbOArk1ZPu^?Lpoyb-?sg/#_-*,6K'IGQ0GQ=S~@;gve:d6yU_=W%rI0Հ^6lٳg.#Om*,VK9$#Hob"3i_+YyjYI}a~[ߕsu>43K:|LRKmKY3f͐o=g%6=gOa{xY! }Om;r/\__]T 6?RZ;flB[EuntY%X) k(R%T(ځFbVZva+Xp"ƥSEWg;/-[dq$ϔImGb>Q=71MOSp\p17n,?6adV1~]%i3L G"/0b4?k/'jͪ[Zt}sj\DDJQ]N=9{yhs.k \PjLLO`l[*O ? ~ߛ͞7i ʿw&KywQ3a k:O18^0t?O@ujغg0TQ=i6xcZkU^?\5ɦ/\NM. ghy1Elk_o?g*?u1' 5WeOb?(g? q&[87q1 sӹM/yQ+O$ :DNys7P]ڍP%gP6̿-yRӼנiZ3E :(i)hZ#1jq0_zo^keҼ0HOP[nRyIԁҞq;qqm5;Ƴ#F^30U]q9E^E4-sWzŧV\B 'n,*w{3ZfZ]ol*4n.u=IPTC!0\׽2YiZs_D'ๅJ;<'{-iɦ5D#yVFsTg¾p֎?ɱ b#{_qsѿ%Dɝ/<ŬhP=g6E1?6 oޙeC 5mnS?1-67Pڻ$?~1C~Cզ-imax%Ɯ_ׅ&Bbf_ƭ{sAEzmIcK^q#Ċ`/-qy%IP,tYFz5\yo7<ixaIRoR"eW;֙4nt+Me'@N3>p}^EUIo&%vQZ::dT7VW鿯7[)/8tuLj?z:Xx]_N,i Hڝ* sf͑~mMl|6u֚K挥J@`|0H=ޝ `XZH $ 8oML5|zMq5*׉7cjg5M Yѵ-VH>g[NdрeB;ɿq#JKJTyR&0V1ɾ'U3f͜rs$?ն_Z/L<#L6{O!?)<lٿERKmKY3fͅFs-ΣeUe}4v@Zg$?% Ckv}bcXɾxLcp) ^j5כ?MY-څ-f-3IbEӢAߛwhZ͝StޣQրl)t[5vhޏ*h\n#>BEqMK)^?Phpk?y׍?;I)oڏY}?zocoaԟݿaoo?6zw<9/*U=-GMfN@? e'dQi::?]3*gyT͛L.:c]1\1/oKH""PE 'V\K^ѷa:lL\ۙ͸ 9`x{xOl>La]>GggWR*erjyFM+R5KDӮ.-"$n4VFޕ$6ge3:[Ʊ#= E +@vŰk s妣giz䞕Ke/mNFuNd[Ζj>mĈj_ҍE5}M:.gc+ [g͛dWp%$ԹE6l٘CMZg|% 5/8_MoM9ՠ GPg3fPx lqEPvg;/-[dq$ϔImGb>Q=71MOSp\p17n,?6a\߶mcҼoIY\YK-YQݼv+z0TH3dS~Z^x!ǗtbOHk&G,hjv_r?*&$[,麧+>d1e h6,'/.~giPSӵ6k9ʴ^Y5Uܱ.?m3?+?4S!'#%<D6ù?OÏ߷3sgs]ɸ]LH?l0_vLy5?/@C4[wOL!3֙g6?_%l~ngti?ɰh?yq&?YXfȯK/5&L6x87_ \y&_*{__c^0we͟i=;9I2oQQg.Z_8rJ:ïL<0AT3?._kv!͜_F hz\>`d[]{ױt!%hU~Tߘ H`ӯ5m_Ԏ!EVpYKAʇѓyHS+oҷINP\KmnQDk ;45X 6ο`^yJ]TkZl6Zr$V'S)鲱G]rCQiRjsG^uu!N +d]J (wݽBX"H!('xgs¾p֎?ɱ ~b#{_qsџ%Dɝ/<ŬhP=g6|bϛoC4pPI Vo#BJ/cү&m-t-6h Dh-M ,(?"l FԽkyX\FÒ0e2Њߚ|г[cXgeA랔̀_4y?M9֗5wv?g?hy1El~poo?g*b[ 2WfyOb?(ggvS`g/&Mɞ͜rs$?ն_Z/9$$Hob"_OJO76o_R!wLٳf5sP򽵲2_j~hym^)`IPNAz6lٳg;/-[dq$ϔImGb>Q=71MOVXq8[FlysO8^U7z[˿ \0͞3ցNɏ8^0t?O@ujغg0TQ=i6xcZkU^?\6˦/\FM. g?hy1Elk_o?g*?u1' 5OeOb?(g%? q&[87q1 sӹM/yQ+O$__ya?f Q~\2C9WvMX0\i/74xn,8|UiKm#ߜ,ћYk )D#F̤9 s͜SEY%ޏ qS"T٣o߮N?&u{:[ۋ$i"c.§$^d֢мkREKv)aBA;i4ZҺ3ܙ M_>k:憭$-ud- )Dv?[Zo[O^fñ4Y(C)>Y?+'"iZXԕ +*dC-_rkΝ*%tݣ-C)l`ǩvO+Գ}#wRfK7:pRѴ9yPִ(yDUh W8ggYk$C#(*7a7Okѵb&Y!,E0z L+iyY069勽6|zs 'nuXXk]ƢڜȍJA:YL;WfG2%9Sy:-+I%IJȾ!Q]S9??0t}>[9exŻ3:g斗7K[ RGVQ#wKW>^||y~AT{hhP>"~GI蟗>Ko/h75ܷ^2FIZ0G ?;WfG3~^`hzލ(d`wo^Oo;"A!82K) H>/6ڕe)/-bci8uY5zW6BP)6@?3oGvhxBŖח"QO8q/Y~VsJ|kiZZm$nlhh$7?-U}hZ%ų\IC1Qg|ik4"HەAǰgJ0$ }*U31jV|| 7NC;ќ/r ^k<5x59m..^aTWH“WDF_5Y[B)*c`&?kFo/ɏў[󧕼ѦZ6Kw. 偨`F;i_0&,ͤ_C$" RM2c|i=ޛu+ryUQUIyS.C}v+Ev%O*oMs,}7hvs8Tw_I:]] '4`-gmP/4ټh=Jh(;8(~c̚ds5ʮ#nw/ɏћ c?)4g>6aԮR|9[٩UeRsti Fը: >t7xk0j"[I7*; 8히=S]3S~c>PѬ\4CΫ^G4+3Cum\WevЖL#Pݺ1Hdee;A؃?d״nG}-G"4yG"4yG"4yG"4yG"4yG"4yG"4yG"4NζoĦmÅ|jTr'Zwɧ,?Nowɧ,?Nowɧ,?Nowɧ,?Nowɧ,?Nowɧ,?Nowɧ,?Nowɧ,?ND!.-7V䋑],oQY H?)oabAs$wN 9l V [L(_}Im3С~M=%B7,7 [L(_}Im3С~M=%ȅᦔz$[sŪ+g%(_}Im3С~M=%B7,7 [L(_}Im3С~M=%B7,7 _[Ly_pJ̚eK/I~X# H>/B{Ko oY-o/ɿfP&fB{Ko oY-o/ɿgMï"h7yUاծon$~JIT|w?kך͝đĻଠ%/ɿgP&fB{Ko oY-o/ɿgP&fB{Ko;nm:rf\O,; E$7.&?חѿyI=/WzUUBF"?^^lٳf͛6rsM4>`k;!KN(p PG{t;M>m1X:b$ADo\4MGΗWgs݋!Q=3_PR Ӷtٳd?3Qt k6z|v/J[-l"k@^E(GZj:Ϙ lx=.hַ>JR<8֧ѯ53~mv,{y;`[QR8JV"G|j)5_S[t9mK-6p0[*+|ޚn-Q69\\FFCP޹8͛6l w/3MKX58l+YhRa+G¯F|E_^V=ǐ7!:$FYF[KKGSVqIV"*yˮqմ6ڝں;D5Z-I,uegyi{kݜqk:!&*XlAųf;yd/^eRc0^l*{.&]?ھaՕӽ3uO 9˾foCFC1IɑV>2+B<ٳf͛6lٳf͑]SzInO?>R~ڰ[kƃoH[I-;5ݲ*#r,AU]m'~ آխյռxd׎yTI#2Ҥt4~lٰ.aF3*{gX6C P7W/4dž{ FbvEkYM?,{GmڄwrI4@i`[X$=4xq {һCԚS[In/"ч#v0=Ώ:\r/no 1M<+(QJrEXccrK2¡DK+S;K1pFlTM1.,r,KWqjMw^mz}FRf3GlXMw\[1f^sudIq;Iitݱy擈G'aLG )Rijw'f_EMLD]0K鬪Ĭ P)i[t-TMN {l*1@'wX+מ*'a፛:4]B=KIȈ#j`Т6ewX[B-൴(0F]ɑ\֭ٳa^]ZU7s}T`qDMSb6ۦ0ybRqu33z[346"'$iJyB;yoﾻ*ďvc|Vj;YeX}f91/X[@1_67ח۬aԉj"PE5߾If͛6lٳf͛6l ϑҷ?S3O*: ^W6ҦQUnH4[?4s}5֣gpZV}9Q^M+(>qE~~_S'slfO/I>Ӯ]~U]Zh&I^Cck50^ 24=5t"c!qc`RMH:+S͛/Kn|>*|-ySX⿛JNYz,±?rVI]4&-N}^X.qy Mn4omwNuMumkk->7 W`,m1p?.a.u/iz%ݕPIGJWv'^,{{[KWdJ sf0Zjb +'&;{A(`Mi Oo/- GA!H$*| ֩sTcwoG==5j8W}0RƱ{i{iq+~[e$2\nz-AޭOJ4ۻ ;O!PfԫUBOOL("!ɀ'ydc;W\ҡ+=Ra4⼂"T_o5.͈҅ %N}LaJjiקMSOa (zRjIՋ&jߓRifk~NӘu6W/p'ρ=4R~iZ9EԺtd|n3 I#(.)͛6EϙS7vt 9uG{b{{.ڈ?FkoUD Ň>Rg=|sGyoRIzṲ**K6lٳf͛6lٳf͛6lL RHم*=U~c%[jmk]#ipȀ1n$xώ GmsjFM2OWXa/=]+/JST漚{(g]GEczc's 犲HyR!C~9y+6΁}H I4˄ŬQېUf:l%ƥmMVKV֗,"|% <2fk'LDžU^ew'ko=y-?1#{b鵝Bbw:F[4u/2뚥wh8V%K*ƼX ^T΋g^n_,,`K-W Hp΍-:bZ#.|zM\^j78I%ġUQRhN=/kBfqrog9<yqi~6@ ~;O=A_nR 'G Da35)heΝw^eFPĒ5DJdv710Ѭ .SUZPk\ Kqq6֓H.}ELyqEGK4W VrQ\$˟-r$b-UXfp1E mma7l4pmXlWSJE{+H-d8cWj4&aiM5X JFVVc5噯5(aLA-Aw%vWv&kҒDVA L8TI_cAf͛6lٳf͛6lٳf͛6lʺ_֧"d+2`v:˟1yNTkK魖yRqo,o2GRAа#eOգwaIy-̮`=5im,{KȭN@4]-|1h1fOcI~ƭp_jOŦo %VH/Y}jbRE%Z5Eko2Ix+HEN :gjP\\ FRB C omF}?_}b8@WqX/8`Ab='[Spֱq2QMZWpiz棣^j[Zir n24ְoq>0*rcOK-ԡ8uu{p8Pi턞bc^r[nt KkK5шBp}wyTlOCx)BNdGCɸ?f'y,v6k{,bx*Iw,wFw~vQ\=ţG:v{$yTt]+TH4&%&ȥi ra#-R(6yCߖ}>+]-.4ZO{s$1 #C6݆Ku)tY58Px -O!m^ƛi75RH[gm75oWƘ,yLTat`Ӌ7\ԱDG^,cնɮl:'xnbdÓomq78帨K{ͼ_Sm2Gf;`P tኚ?-3_pi|Rf[[[Ľ3ƫ@P;;?2iV~`^BR 9ID}ֹ'~|x4R+/+^^M6Mm}r"i̒B哟F""BjZPѹҠw{{4dUh.gR@ (͛6lٳf͛6lٳf͛6l:_\[%喝hiX H!yfkpxzX^t+Yu>9^ i{-?g&:_|`l^:J1K#{-e5Z7ws8-⪁U˄/u1ۏ/$/0 $-̴]S@d^U󆽭4[z1kkBN\֎T\ٳy/-cy7/0{tY#Y횪>4zk-[A!О+:'{D:,; ׽p˟>fPTWUKoR&k nR;I}cӼ0i3,1v0\BW᾵ƿUKr|0?˰q^ uO ߗ욀w ^m|/q ϩh/ZC!~Y2͛ zR7?0m͛fiR氏TwP6@yQ,m{ۍbM&{yd $e8K*k+9]zx$r4Oy+:oc]Wn MgwE 졅.nd*~/a<=^iE3i6svRFn"(xIA#f^IGQ#e`Yf]nFJ3f{Za,ڝ{+H.4Ue1M>$V^C| cƧ,:iOжD8>e1_N'Jn|em[Gfuk?0W~y&_Y8[~M\q FsOmI[CDF%'3Mv88Ǹlٳf͛6lٳf͛6lٳf͛ a2i,gk&ZeI/1BM Ƨ^F7 +hA .[Hch#}FWSQkpG}i[pMpaŜ0 ܘvZ˽9Mh4Hml$U>w8֐[]UUR2fJkCN3]Nk՚HeՎic/Tl?%i-jrjw:~z#\24o*Iโ-A4̱̊S[]ΏwZn{u3OhhP q+~b?I/MuBOvVV֊+I< M{N7K4쓨W[( yd8j>vcAk=ƛeXK,]DR}E4kAF(vwN܁ #kQHw=܄_D\ZΌKy|}RXyKogosgj1\0_. 4Q J.?F>"e2Je[,ܜKHtf=CJZ nH:PX*D圠eKC"`:koNȓfRŒc*0TGt:;d6’GF52'a~,13Km2ZA$v,, OSOaZ}Z%osw;ʉ%Z]%HDRÉ$Uv8Bt;xToқ45SFƦr帒ᯮIgӮZ*sҀ|~>C̯]V{P{Im[kON%0-NȨSo$^d5^Z{kX h9,DOb&5yUC^K;h%@."$Gqtlٲ?7,odUXF+{zѧUP˝/ַ{˩/`7Nc/! pUI$V67sIkcX-ˢ[Rאmñ?/i j,vgd4V6~]0LߖvisŮ^C1*?1F謟;X[_-+x(=zkhm^ٲ;c~yjxniKyXmn{mӎɴ-7i*K/5 lH{-JQOZ$_B"_$uf;p>TRꁔB 6DqDXzjb]/ Y5ŋM Lg2F:,Ev;z^hiiH0qݹT ߿\=͛#NP;A/jRAֿ 6[wI-V*$m}y}l&Ȟgͺ򽭖q3I2Km,Ok*Fn.bƪF"/΋^\M=6#[V9h2ȭ ֔ pNw ֮A-И-eHKH۬Ȕbq4sf͛6lٳf͛6lٳf͛-}'&f5m.-cՒp$x[M{*;OQwEI ֘SO}Cʗrhz>dFH h8QC% )-.IxFҘCjr5Mb(X"[G Щ hRbߑ8jz 0|ooPqOtoA\^|jХn.-cEH[rYbhԴys?P+[$)q,2 ݾc_TXlhuuI+C$M'xW7MݥJfbp`бهe.|{ ѝ/TtuD..)ϫ-8`^K54/heWvx׳&Xn@BPFIj5XiZ0uImh-u>ۑHl"eDR9Zw-S \Ŵl+CNQQ๑$cfYkͼ:uZ.t}@Zwu `[hWiED ji2#G{%[D)`cU"Jh~F%kG_}w2IQ,zlU1/)35 +[?RiWmVe#6Oq ͍n+jn4OQY=OWHQZ]^,K%{&bxo}3TǦA3Q.y~mBVV)tE}.D#jr5k7[w%ybY̆ wV GC'Ĩ%P_aѭ0ߛ;Cl]W zim;Gx;@m-睅#P21j:7v[,5i] :~Cs9w9ϙ/t(軛ƿ֔7(ʱ*p̟WhtKWyK:YRYR)tNAFܺM˩r= O5IXt95:thy e~"ë4yW.;X-a'YOWP̭_]o1=6+|0r%+ jh}Ec覴ޢAo6~aqkzkX\[fhB 23jjg'=&@Dbs(v >v" 4O8[hw]X_rv@KBgZC-<ͩ#˟gOiۗrQLAv& Y[[iΧ}#ثi&~$rR 0ntxn<qK|wl[VtkH^^ie G¬}GkE1jZGfƻl?ˋ+Td:]wckI`M^zмj%֩n򋛈0e)Y"Wsf͛6lٳf͛6lٳf͛uc+ogn!>ʨ+3fͅ^Q֭^{%m@Y% $UIǷ0i+[{YnPKopѷFGYO{xmⷁpBQ(|3fͅ>]]bMaloa$+8G@Q#gȭ}6tJkVxM _L6lQc.j26vkVOԐX՘A8oiWG+4qKjݥđuu`ٳf"QK$]-PR#,jOdalٳf͛6lٳf͛6lٳacycˌnix+*K⛇;&!IDtYAZ+،~[yJ8nNԧ{"isM=\3o)eivřƵ/l)>LJl[;}f}bYnה+4ߒ"R򻾞3"cPp:I۠3EA=2Cm(I v`ĚO_е;Ym9"6gZORI"VFn &kcH\n(ܝsDGpב[R04eXpʒC-6O/ก( NJܞU5XɶBѡѬ{$D`]}2J@؂I6\)-h^8Y"Q'nRaƧheڤ:B#^"Hp)?g{eBR]/Gyv!OVTdzUî)wAiu>G]\x ~ 21mY5,o[~\誫N.bP"ڴ>[(>P/ \Ʋb(Jct{-^(65B! f&8W6ZwbMIu"$obo&xKd `H\,+OXs엎Hxq[)Eqv0$5HSMw,ysIG1Zp$`J=ʱ,J>^3Hlaiizpјubrۦy#ҴIx- U%֓]sukưK"d5b}?=4\}JJP^2>&,$nUu;xY"Iq#ؽj-k #MHxH鳭 ykдmXqK%cVTM7^+r.i #,iAP -}*ZEQ)^1~v?-FNpF%2Cm'Do٨b0ʞXlm3J"C6N%%Qh`}6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͍X cupUhb;vl؄W3EsEDuo'M^/6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͍X8vv (fnmyeH U呂"P rM:G@%Iٳf͛6lٳf͛6ll%u5N>doO#SdD$mІٳf͛6lىTS?K?OAukp & 0ބ⹳f͛6lٳf͛6l?w;="cm&>+9XAE=#?35_G^ŬCUJ:UI4mZNsߗߜZ[4x!҄OX@KqLɏT:gR)?)-2@[,9ەN}"0_̸|"}Ee%~L;F/~łC˷vpo4h hЂ?iES^様E mI#u5zS.xwO'>-%Mi]}U#[ww^~|3Aib9ONSiL[ȉ/``_QvMMdKq3\5 HU|\ O١43?Z4\Z8K#CF<Zm\ƃɗdͯRG V>O+Prrzsv!W^Ɍ?mj׶1ҤHӇI=U,&~^`B 浆)Fi&n E``w`/+nگu1gCѴ..&IIԅ*7ݏA%޻",\GA4gP[jrM)POWvK:R Gi./m^ [F78eֵFwh4QqmkZVJd/v򟝴0˨XִyDqցrFK+"{ٳf͛6lziPJ(!2XRPoa9!7Z_&^Gk-W,YkCvOO]UtMWt{{}f.j0i@[{Ӧ1}Y{OcxKEc,()ǩjL[ KieN$|_jrqǯ䛯)yFJ#SEB~1д,=sjZjWoN%.(<ůs]ۛ?*ir%9䶍JʀujT Oxֿ&?2tXQ.:mr攴T:b: vX17$ZmD#$x*z+^د|6N-ERc LׁUٍEw?QQH';DhUl:?|}޹g"9/UP39a p]{kȯ&yoZMRHSaOZKk7@hv9̯"b_.j6ӯ5y_RZQ,qyUޜ~&4Y~hryn~k%>d`>Ƨm37ɚZzKƳjvO1:YZ eTאZaDG"51O*FJF}1ũ^&|FoiX3# 3Pq[󧗼5;֚Q5 i `yA($ʌ3?ڦ~WӣtSM=5F`: i3/kgG0"?}^R<ݣzxm6åF:!Evޙ;|< 1KwxݼVKe!ߥӚ0w]k?7:ޅiZ[q8PS+3?ep2OO'F=]AΉ6xRҼ9iwUas4XC?t&q]y̼IFe?I ~rdǻy-W\[T9%{R1nm-3yRG_pPr!Zۈ'ۑ&_U?^HknMfO:7>_~dZ8CχQ7R6v:eQmRcea@h3yH|69Ea"}{inf`kx-ⶁp@QQQ͛<9@>P>'9|,YܫIj#`IVRw+힑y-<8ޚR]BJ&C|2=ߙcki HLOs{@ImCNBO_Hdo-u|=ߞR,I "WԸa_w_~4fkE~ն+k5?KL5帋sKhW ;E*rj>dwi>CK1Cp}K|4Acq$Ըs5s1֟#OΏʍ#K=V(ux4m+#8b2?hw??"!.L/OmLjT[F&#Roȏ0Jk=g=5 5w*$nj/23X~Ozf×*ߑW^DV[;B^bmS2]Tjxw*$GTYe!AT?ꜯīVɹ27eSU1n@wkS7?~e;\cPдI*qUVc&$#B˓X-D`?}Ŕ>BdH!*HfyʇrR6mo+ku!gV-ˀGqU`ˍF?)J+n+bWᛔ c䧗|//i30ho: 4'O˚$~J ޽wkƯ Y?΅t;5y/9Gjڞu qKhI (ߵA=.ےo׿I"]qȚ,4 gYS H\ny#6㷜<ߨkgߝ4O5hkm5!I|qgr,oGmF83\(%G)<<Ǭ8xv^O3PIө<2kW"4ʧPEr)woc// 5௢ȲiyWu/E yۂ=~e.qˋKҒ. XxBJGR _:__6~]K[m$Z77flRB9NDnpp!~ecywŪ:ɩ޽ mV䜨t5,O6h|5[\hziI@]W<աhZ\w:4ZcBI²8@NE1.Bpc^=|y|_ w.}/-E=o L򪖎&` agc.gO6h_8ȡ\,̨9;,TDXfȯ?,<{X|ϧpY3=D\4lAQOKI_S:?y[C+QgZ!mً3bY1$q_2mb[;UG׮THVbm@Uzxhhz6Ӭ"B .tK$T"Ȼe[ѵWJnK}6S3IA+S,fIcu(Rq=hF'y3C򆐚>EIYcŘ!0;Qt9=~^iY,C!䬬YH=wB#VI2dߕLf{yjo=̩430R$vfGJ`*_mΛ{;y^6RHj!1˟+nNWIo.)$eiE[AQt6?LF/Ԧ[h:e& \.^+%dH fd4( O痏]~}X\}f^?Wz~-L?_l>lN[`u"BǓD#Á;L}ߐIu[ZtBh>TQZdFp6Ǘ[Ѵ 7 ,=ąIfܳJGn f͛dH#, *Tr*@5.[txB=xG*`y"JKԮ5Hi)f+y*M1=c.rjZ+! d^\_K5}e#5̞#^`5dJ"`CW ٱ,8n 9AE H^妏:Rt0SN-n !ʄdD{7U4en+7 y,LI2wΑˏ"TuP,-&J :٪1^g.-"NRD%=/ɏʸ 8bD{j@pw_I^WѭetN;^۟ _+[K|d'P|0\\ ?.<&Ȋ4Zx0oTT0-6-Nv/ S(E q Ӿֿ,s`&8M{O,b(@5RM Ůyj,`+}_Oǡ"4de*MA-[+:'^+Ir;|n׮Mnf'ڇaAշhv~YԳyrB|嫭r}M} DKÁ4iEִoJմӯKmpz6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳg)Z<ݟ//^~Q$؂&E<G\#-3@XMK/֚d kKTHc[bVY€hC0 vֽ-.TIggցeT=F!ZǗFj {g8ͭz* _Y5eUh75?J]?r'FZjePG9 Yk:U֍6׶ZYbb =F _\~X~gy ˩iMd${iF 90͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l?iO 4~Opz^^a^FC"@ȍ+#?,WizzŮa 5&̰A cu'Ke=O:kڤPڱ ޥ!1f<%04:ʣu1IscUVMr{w_Ϗ͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l??ly?.XI#Z'fBl-u0~hi^D!X64+zV!XU6@/;~dE(-D˞dҤ*}J+ GQQL_\9[Z~]'[Wef0gP;y9|]\Zd '˛Wl+_L3f͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf́tHoJ4]܊r֝;WVֵ'en_$&8 A(y>mukCC+X-u6sL?e4j^Q3t6E-Ӭgͳ=g[Gi919O%y>r{wd4Z2F^0̒Fj> \'j|7$[ɪB @d>U\?ߓժX5Jlۑܖ8Vvym/h/[ij3jvpF5)C]s~Cg'f͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6s0SdV)|-`X SO# /£92ȷ'Ckywo.'9dYhSpQ_2t?g=)6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l3u_2y_twۼ6ڬVJq.e*)7k#EWڟ~qxͩON$bb-Gl]DNL^D i;#;TPK14˧J+_NheYcyƝN4N]iQ^[WցD:"@ӵ˓OoR|6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf[eK][^jvr;ϧ^?!ЫV GZL?\&Y.c{<hf.&,edN'w=KH!x㗡 2昮!mcuh/-bІ"7W$1椮4WK3אPo"JQ XMoCug]ɇ 8C(:3͛6lٳf͛6lٳf͛6lٳf͛6lf&kyl;ynbIUe-PF+aZM?H/ [G$UU$2C6lٰ6ievV{$h*v#+lҿ.t?0ZomŬ*P ^JH ٲTI;3ο^B1F? gQ )nD^=Vڽtg^$No/vV[]ݛ9ﾣ H\8o^_EMv <lSj,/S0g4( SLyQkkI#>r5IpAE^MgeO˽ݸ[ZšIc|Ft[:Ula}o [ kFܕ|6ΡʾIޫoy-nj% ,G;_E|1ɜlٳf͛6lٳf͛6lٳf͛6lٳf(P~HcFu{B6Fۃpǟ>ݾ,5HbI47w\HlME͛6lM/+Xo+=J/Fi!*$U$`»w8LykD/HZf7M妋wдy.-d{%F~r*EAJ ٲ;f/|ڝ%Zh+@nI#ĕ=:|Q=_Mn8`Vba'swʭ:m7FKmH#u:Sf6r#N@~|_wOaZuƟ"<'oG , GM;/gOsf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l'|{қU YW0#VAŮƾP|s= k|f*!rI-yʾ`ٴoVԝY> vy̚ZR"nfȪ 4#B4?Hʻ?/-lgw5y/}g;IIPmAFy6PiK4$3Ѥ24ve'iC3|=g˺izmе$0;`HoqE|1ɜlGw=Tm:yI>sK8N˹KLu-:KY$dXlܢI;V9Uۭ(p_,t-X+{a lt,ٳf͛<_gf͌h`E$yP,XG-8Gon@2qbWK;ֽqqra x0F@,<߫ycզK*Kt9cđC@WE@"n^K{2/-D [֑>5탇TR]]ivUaksGύqJq"\jPm?7cVНlt q5.j^!X'!Rjv5V3Ek&+}jEiPJ07ù?2mFwowzu)#1%{Y g،i4~qu&BAs3se?U}KkZ^+Pae'rTRZ::ms?ZAu@l"7D=(A?cj0~j(otȅ4(REDzdV˾{}>T﬽}#TbݱFVY͸o0\74iij$o% ,ߘ)yUӭc&Ca%a>İVY\uV~ PA u94Kx{3=`fW?N~$mjb~W[ԓ˯iFCg/4#M6Iqu~VyL$Wz^;dk=$R[zkk8Y/u/t9=ʱ&Cj(sţV W^lٳf͛6lٳf͞`ǖG>k5]֬cI  :{<͍kA{"L }t ac6 *ѣyU$#lP#͞k u7na7fF,v6l̟Zw,v2HBqGNE5-s6Z:Τj]kz|0PӣYu{_{."RԭzT/6Z~鯯f[?xQ?ԥs_::+{qy$Q rm@SFگ0`Ӽ[ZILzPrLNISM]OigH4 0"5 VKdcKy͹(#juΡUf$X7TAr$_N/}mCg' P]95 k7ME@r+GE6$mA^Zz|¶pi}k uK+Vnrkm^)a[뗚&PE"WD%MhCg'<#4Vo5IGcĕ刧5?~GiOyM6%a$'")OO=Pkf͛9gø;|G=׳f͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6s0?:UԒy+P52V.f `,jV+M^:d^-#cQggH_޺.f<+sMjo2<.ݻF+Ӂjj½5oihvQ%w[4UFT_-*Tb _"vgtFSaIK6WA4̨jSu#ʺ y\KmtzrJ'd'q<-XP=h&_4-OVִ{FMwS)/HEB:>/C&sҘY=9~ղSgfwTRBYu$7?,S-*OWg!';h"T)ni3f͛6lٳf͛6lٳf͞8@Y0ߛ^Kt$ZO3ym4,E$~3ߛ>M?t#[O3yM +RNfK͛8?KLSG5|8K8仿˽#:E`ũ2YJJʴ5g* &!=bBUG7ܱ?1-6_,]wo;%Zpx|C9{ey[;bYݪ9!"#2Uymi9޳aoaצo'Z"8gZ5@y>cҵyt<-hv:dKrH`[JӮw/-CY<]4ãA/A+EAJJ*AH^R0EV qI$r x:#/8w/JF\~Cg' [5M&yp{eSg&s.TƂ 6?'$2M2V$";u{VTWGO)bZF WGT7.-&h$95r`y'?f]G5u-RimAs7j=+ASS6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳayrO˳ӥӵFc63\->3B# f4)_No6Z-խ"`>5r6`OJgT,HP{*Y3$αƿi܅Q'"pzd32sE*G$!FTcολpQ_2t?g=)<hy|,T\GOMߘf6o?1MoҋOJkyq-^ ޿!KFX3C-i|$uʮXVe;c=?-ȟ6"a'}_#~\XFW@IUb?(:J~o_F/mtBh4HB3?t!*zrf}צ~g>Yk vq 8oaYlyB_޹]Cɚ}wL--h͈O[y6gz/%~S}bNG|'O3[~ZyoSԼkuyd9&x=9SuWBmA.[H0?K͉\Df!~Ԓ0U&9w>~L(/啭J }*kM%7d$C;v$_oH<5[AjR1졝%@Зyg{Fk嵗IE&5ўdX-x3䪼fYg#ͭ/+bھ%Gr>&Bg^7mĞfյkQD$_MZ:u!(?6RTzN;|O2ZU[bp֒ Ԩn$Ҵ8]i\in]:؅42Qý#]ѵ2=SINw"nQm#"7i%iZLƥ{^bUrj˜C~lZjڌnm>[C:<ԭA>g󿔼bmݮ_r Y7nk4V͕*4ļ{Dg_Yq~Z/-y^g{/0jvqa{v@'ƌF<),on,gլ,^$lUz)|ǡ͠0y OuRJȥ6i(c*{O4~Ta+8%W w p_?gգ4z JUg51X&?({7~f6e!gC-r dSđ[+?&yn:Z(.A%xW^' 5ʯ/:>m5+6 sl` Hz0_/@^-0sU"6*0Vٔ ?`So"M54hZt-x%0 ! ۖ'~R뺽ksH"Cph?1<{k3j+x2I'&Aɇ@{?&~m~_y{-j˨]E2qNU}?N?CU6z" ےdï%uҤ|wkw$tX$U=dGQӵ >\1\GkHث4#M^/bmzp.{RRvD6W@so9˾MѿL󽽇zrWf(~z~[\CЯfG8%oDU#\[yyKqӂBLJż/Y5_(kz3 `Nt8>ߜ-ZǗu=_*1[Gۈz#nQU-y]]cM%[h(ߐ&] ϖ֤4&Gs^ K8wn5-Ne^yɺmSִP R'"Vm~][ZmޮU4\I8BEx}/O2Tw:͸UKFm 41! 9wO&-yDUW;7掯!5!u^\/$W3S0hf]g^4G!dv*UX+fԼǣ6hW^L T$Z|[ۛx,KT"`*0r-iNsm,A//\-}[^_*<~gTg覜Ȳs:SZS^~XiZ%EγzRZ,R[qPBkp]E^Z-žD7V=dQ<_˝S:}c2AY aJPӶ{Zǖtm-$r5¤|LiT{g3|kw:go'5naHZU dz֫rSP5 VF}"wW 3*u~0sMO/K-C'v!"v );\p^TTv#sG˟ZǟbW7%VTR,$Nv7Z.tDZ(a3%iԿ/gehyvRcrIp}7bzp%U0z͔1QɀbҭHlQfb!~GuK{80q'¢|.ZdwX4턿_XΡn'0b:ʿd ~]?畯%CoThY!-ZA) w)" oDyƫE]K'3zo5$+-O7h$ T34ywA>ajVBOFgn-ŁΥ~\ A]CE|ȷ6 Wه%sɞRmoFJC%ȤԪ_-y}fMJੜZB+PZW_>@勵|^^yOs=RH*Ia:Mie6V`E%Ij"7&N-._,iFЭ;m!B=ȯ*@(q^XNHc SBu5]:PHI1-1Q jW&WJҬ%xI%P-kĘI>TsKG )d:Nh1[]N&l:mBB Uv燿0?=qm/]2vbs_}O& zGyM*Q y#(TPgN~ND- NI#!BlF^]CPޔ/!`Ep= )Şkm:n9*>EGxiIJ4Xi:VXYAf$AEʝ9pOh[K3$6crEpL-HaZ5 (|VOӃd"0DPC#D$vj 1KK[1u(jjbBPhH.[+9G#Ҝ>dcW1JMJ +i{1f5$Ƥ~XG# `P 0Y0GC>Hxȡ׭?_?&|1WonOhŋK(#0);ڇ]h 6]ZHac'vE_Z e&A>4ٳgjdѴ]_:[%ͭ· &Y*Wua֓kikZm}\J|Eg-4iz߭ǭ V$Z\|Z~bz--Fr- b22!h0f ۦF&.<r y͑'2a)\k$OumSo6;3^/)dn'] v4sͿ/#F5sKKOMnE?c9?μ.ZdgZӶ]Fo5XRH$Jr9__Cum.o]xyK& OvO6w3d3ϿD̚ծԆ8Ci̬jV=s_?{vnKmAn%GXC"Vua?Gt*T/,l-PZd%VgJ&֦.nWԚHPӘYy-M*3S]mOO&z6l .0I9'Aŧ}1S8ne'KqtDž=ey[̷F\xΝQ9?w}-G&K4YkYӈOG)<'EС1zeق?/L_zouǭR Pȟ *Wd^Ɇ_izf ΪTr xtUa(ֽ=?.zz|"%^v񽐠j|-D'xwrޘ~gh>5Q|\5HQC!HNu8W¾OFHMBLvS*5џˉD i)SZUp˞kC.o՛sȀ/Qfەr;[[j_] RK"¾":ʬCSҿ!j[{o.Iake9b,YQ#5\͞Y^~3Ӻgsm? sf͛6lٳf͛6ll=GTND׌ݯ?!qPA3ykc9|(Wg&f͛6qx- ]5헖X'$lhſmmmׄb ܓ7~|ٙAf (ܓ)YYC) pFAh59xM_Cug]ɇ 8C(:3oI0Sё/'g0ğ#.</9?΍+Nor𭬣:Կ<46U>s?nگ)fA~V<'IO7Sٖ9skP]+AEјp<8?SZ|~[!J|Y}/9dp[Ϳ]2qdZjy3չ`]W9wOϛ>C׏-cޗ ӕ+H6 Aal?wjuC=JZyXj3]\E$#1!IgצN喚+g,|? uS|Q[m¼!Y1ĵ&EOϡY#ȼ=<ѯj/fnW%ҵ(&ð&czV*;oJJ/):?7y16q1 sӹg?;JEqrM{vmy4jK#ry>&'͞Y^~3Ӻ_sm? sf͛6lٳf͛6l?}[\G\̾^:q?>i鯝0+#҉=Gt'zy5484O/$]4v031;9ySNTc}s.O%mps_w宇3텔rpb-Ƽ)ڹݿEi*a[it}j0I0 bZVU'? s=74}CDuE-6[rHH9oeE7&O'F@-H<p yVY:IIjqz<=C_<ˮM5A|e\Zt?7]O:kfjWڹ;6D7Ua_0\6e0fImwgl͟i=;<9|9ο.Z_8rJ:9iYo U^Z3wЎw+vV&{H'Xwf8Me)c:U,äecVn<0<]+iIJXG5Dd9 8d us/kSW4"a G=ªt"r^*2:j ?גקip"UYp–znC.-Ĩ@~~AhмרiiV\{׼RN*ӊ5?'mt\W/_)yOxCT\eo_i)1AR; 쿐'|lYImCb>#Q=71M ?)??֛=r$Ϛ?/%*Ov<ٳ͚~zVV.0cOHҼr[;9!it94ֆ,tNZբԅ]Md^Ƽz9,?"?%ⱶl"Eaϱ u@&_EMsTBf͛65;+MԵ M=RLƀ gMV.(^pZz)]B^\O5^9ޱj^͢CbjR,X_0:g#$ߤt[- b 5͛9է䷙&Ӂ=Hثq{ՅFxOu*-A5e,dq$u <0^Zo6mmǛ_X#&_Uƕ;w*]#w |Dh%LYPn ?RKmKY3f͛9W?.t=KMt_3C}vbxv3}Dt h0'|{-.6W`z5"C؜7z6q_ZmJDk%U1Eq;۱$+zd5'dt Hm@il6iZk>kH~jkA^ä(jޜ]{Hƣ4Kl0 +97ۦ^jzVp,Y(U?/C&r-9)7? :2ykG|> Jbz^RZ=@$~7?;<A%CK7i ʿw&'IO7Sٖ9s\KimZ[!(O|d̨ҸMOmq/Nqm-$ZDTqNz枭bJ-AfG40#/ Kukiz_[( 9N$1jI) ě'U]` sא1Z_ge˦/\P3z^^S}ζ|.֟<'Tр~}lWd^ɆTC7?Isg/=%_ΏE+MuM18;o6EB\ld:Ji(K'5gsol=2Uymi9޳`w\-Xf}f[fT$ G57jQV =kk%2XT=U8y{QvmX{[YLg9k@7tO\O'Z.zU\-֝x[k+ڠ0g?7=Or3W^I*~D#q2#F?\%Ǎ:H퇖ou8*̠~y-;,?+#%ޗ.ZR"b\o^Jկ<:J_ўүPCA5*%@$xWf̀u[ѯt}AYu^1E*0lsK[K 3{4/uzTC6{;ȃZ "S99j:=X-S*8vso;Iln&n#^)V ej*'4O6'n4뉡hgyRT&!ɕև;Nl$|EEAz"EI:7I)>?r19m[P?<3ϾHOMml<Oik6e<3b%t흏6xrsZ I[;&&6Dm$cRImmPY$USNO?/'ot+ZMOrZ\@;{oH.b}ީ\ZOW:dW^|OwW,B~=5^+i^xhďKl[}yg25?2/JH|(eb&德Iռ)氆y !U|NС/8eEƧd6o_θ?5t/&;c{X$XRԡڔU͟?|/|Eaho83K/S) "aе/0XYOuu?3HL|*(Xw<çi&Y{<9Ѩ䍩,?-^M/ $KP)dpcR╮@qhzͧ QƲ;/T?3sXc{БFGպZ͜rs$?ն_Z/L<#L6{O!?)<lٿERKmKY3f͛*"/4֝_\yd.a-"U*|u:s;:<tgg-Ak{H=DrοwNyI1^&B+E-ɛ˫TcȞrMg`3i:nYs'"k2ʭWCs8瞙^~X潛Z&hbcy9+MD/C&r-9)7? :2-D6é?O/N.[=o&MœO6w3g1n-r8zwC?/@OӀ+.Q[↵9y|7?_d˼|69❗ &s&kʿhMۏ'>fȏJ7"L6x7RK[9u79/^Rt/9[ncmyb-?sg8ϔ~w'9VK'IGQK'5gsol=2Uymi9޳fu:k?yv+V4AyWԏԣF̊\ykFF- _NT#Q=71M )??֛=r$Ϛ?/%*Ovv21ELy_?$.<:Ԁ[g?j&9{JA\j 5.8vݎK|%Lx^:S]%8L=w6|?ͯS^֣ߘ˺Ȑ݈Hd*dX9"q^TXnɯ۱s^c8R(FbN,Y?66H PX- #~bx;+\],rp9"$hнL7` \HyU#׾z $ߔM .0I9k'As?ח.z[qW$֟1w:m~c<W qlWd^ɆUC7?Isg/=%_ΏE+MuM/8;o6EB\ld:Ji(K'5gsol=2Uymi9޳e:FSZ0 Аw#qYϝ>@=Ig??Ky':yϟY[O6z6l:~g,"//^Rtmd/fC l$|EEbJig$Ai-D_ay If2+8o_j\"6l¿>m|ťkc@k Nk$̏ U}4_R)uEuy\\U_X׳f͛ (nl0?/C&r-9)7? :2-D6ù?[dq'g-CK7i ʿw&'IO7Sٖ9pN=;ac6=Ga8eu=Ho>/~S6O.'@ͯ cgːL^_Թo_Z^o_&mAdG%_y&<S) %έk:_oJ/):?7y16ȿq1 sӹg?;Q+O$s%9Atj7C䪼fYgFEe^X-o/2~#Bw#syͬ۶XٿL9\vq#n[QMjM6mOj}[M5HA-#N$ u#8*W2\ZMGviVT2]J?]پ|et뒴%Y=TwQ4lC jgJ:[7shVZťγk:)OLH`I:w7I)>?r19m[P?<3ϾHOMml<Oik6e<3b%t흏6xrsZ I[;&? (0tß_LE<97_+oZf֘͞04ì!Z';I}#b/?!ggfN8nQY.ȟb"ME/gG&O"fk_0X]99G̟TY/˯D?֗&rIH֑E&=Οnl")%B,f͜M~RZO,0^Yn$UE$|$+ڸiek<:ϛd]Ȓ(MKbc(p(.&iv'կefzn#AygyS{W7_VZeg{pyZIUY:d_8 ;Ky^S=Ks-P0fCSεGo,W7Z֙;A5駪ϛ)B +_L[sRo,td[mrtՐO].{<9/*U'&m?6&3fcOf[:pMp pM]Jߊv~Cg#%hx&, 8WM>g'?tc_ 7@L9oUY3?8l̯iw3L:=%qs.?"Ou?<llt?+%XD___(lYɶyȿٚ 39M'yQ+Oa?|1Ɇi/%'7ȯJIs;lٳg8խih=Jx5Ykx!Ӿ+UgE?0NhShPEbH%kA\Yoݯ5[MPZwg ]ȷ$`rPt_Hk^@{}-ݾ,-NəXF6/P.4?*ך MBHᆄA]E?1K^[iB>1;Yh[pQ_2t?g"yc`"GOMml:T7eis?yWbY>D3i116x{s&2'. ㇧4?lf׿㇨4?lQs٭'=o&y$Llr;.@?7?M3yR祿Miy's3К7N>}͑~nEloW33ė:rͯ?nsٿ_(l[d_r$Y"gZ%N+q(Ns˯D?֗N$xyoV{<9(.mFv/W֟LÝ6ldo:~s:[2Yc4rS4!$)R?r19m[P?<3ϾHOMml<Oik6e<3b%t흏6xrsZ I[;&?yQKaf?-Oj;yro'V͛<73aPiXCDN.wG^αc➲͛<:1Ed"6zK%lg<{P=c9wI2mQQg.Z_&y#ZGlB:Ryٳ 䤗ڗ?f͛6sM9o.#WӴ8]VnWD:۾ ?tcͺ^bs$ [EIE͛6yP{a+_L[sRo,td[mRvՐ_].{<9/*M'&m?6&3fcOf[:pMp pM]J}͑~nEloO33ė:r͟?nsٿ_(l[d_r$Y"gZ%N+q(Ns˯D?֗N9O-Oj|矿3?{8eɘsf͜o~JǿO˛ZmC7ֱeu" _a#6Uӭnuc̑βۨa2/.y_^eNb@IR@=@󟗿,.:jztmUU[i(5܀ؕI5O*dXn5M7̶W&9o^H&Hi<9y?/]~Y>kZOA1OΜ@ܢV.8Ft_oR|cr$1vxg|(&y?MPmy9 gDŁJy';l0?vLy1?,3p%mWgx0M֙g25?0|(8_H>3~|AYg'_?7PdO?Qc1~U~Iml'5gsg.#Om*,VK9$$Hob"_OJO76o_R!wLٳfm͠ߍ P1Z5¬IFFO9r]Z>hV_i\HI$5bhJ\ի#le{{[NGY-i$/~S6O.'@ͯ cg r=-8kO;~?1քѿq6low/?g*!a$ճm^asE/gG"&?:&7?"!.zw6y[sG{2s~]%ipus%9Atj7C䪼fY;{[ynndXmFi\TDfbzp}Of?GFkB׶<>RbF*ǐ4_T);Lm-dMxI$vF dmoK^Y\^-= D j{vkg?ʻ%iWfȏJ7"L6x7RK[9u79/^Rt-9[ncmyb-?sg8ϔ~w'96K'IGQK'5gsϿol>2Uymi9޳dk*P<֫}}slAf31sUo8Bj7|M-;I1ȊкM>j=Ǚn|c7K}yğ A+)BZS~{6lÿ1P/2$9-]#'6aO'olVsO>hx&, 8WM>g'?tcyQKaf?-Oj;yro'V͛<71aPiXCDN.wG^CgX1[?iYf͞O~pC]?EE=U%_ΏM̞Eֿ׽a͜rs$?ն_Z/L<#L6{O!?)<lٿERKmKY3f͛7F.O W&f̈́u7^u|?c9??zocoaԟݿdq'g-CK7i ʿw&'IO7Sٖ9pN=;ac6=Ga8eu=Ho>/~S6O.'@ͯ cgːL^_Թo_Z^o_&mAdG%_y&<U) %έg:_wJ/):?7y16ȿq1 sӹg?;Q+O$s/[՞?f Qp%U0z͛6lٲ -KSX.g;q=Zi Ȋysڍ.MN+um&`3@a)}5Db-ULg4ɿ*7pum[/<2aV^T}J)0f]M\Ln)v L+'8/SʺrUAv'g-SSwi}ij2guXO],&9=h-f$qHĜ 8֟Zl7W chр3> ^yo՛MYD_VxrNIx2JՁ#ol whxi@Ԓx|Zkwuyoo!M,qBb6@$5g?%5 "ou F-I"VIoWvo-"Wk?Hj~c]K9#Gfs/hF'/0+)؂?eI0Y$:t:P="mzso-"Wk?Hje9'_cPf[~1G4lƗQ1'<{slTW4`YO=l/|wiWnx."-3:nZgOt欇~rZ,k-FI_NR4&f;lbNE"H:R-o-")b$Y"p$BXٳf͛ ^kԴ/֚TS:kr]?e@v䱫qiϖ63ޒiu+Iݤe$b نs/_.K:j:plP^L?3~uyB֬-s]G4LԂ)LiK Z.$Ccm,WF" ( 5ard("Hfg"Vm|>8O΋g>Oak8dNЏFkB?n?7ih#_ЏFkB?n?7ih漋p]m_ͭ# }QN!"d̷0/59-M7כ44^o/wHyGSM#G5M7כ44^o/wHyGSM#G5Gʟgu 2]/G?䘉(V?%#_ЏFkB?n?7ih#_ЏFkB?n?/"s.@h-My_ȟccv#Fc0z9Q4Zx%#_ЏFkB?n?7ih#_ЏFkB?n?0WiacH"$)(͵s>yg^I}#[k;$451emtٳf͛ _~VԵMҡ7:uKMfieĕۛFt.qKyMHk 7HkyR9B?I#v;tΏ<~UyΡtn{[[ ^nD,܅r o?ˏ/]C¾ey?IP(7IqY_*Z x4eкJԫm?TB+RS7 JsL.*U3кJԫm?Tǯ亊*ZSO_#>yS:4+ vyfiToQ /_,V3E$$#*\GwcSK_L__m]%UfuVW[o9o__m8.ʖt&S"󉿗y}~Z\hƊ8H~,о~Lԩg%?OW[o9o__m]%UfuVW[o9ev[ZɊо~Lԩg%?漉ygq7I4l/=Oi3+nr^ _WK YOW[o9_ JsL.*U3кJԫm?TB+RS?pg֖^{׎HI^,rH8?7qsZ>݄Q"&)6BKFy,J8_tgm 4ӧu@XV2¿TDe !Xuln39[9%`ܨGngs=^ֺD{ pҘʏ1<O*To~U|ort!$HR;yWo(L`4./,{ms= ^6hs ;;͛kz,tPKrsx,( r#fmyrv`V;:qQLé|Ǭ4itZxAP9n @]cf WKC6{[@jY_ 3M1fsmcn{s9zndKX*Ӿɽpȳ"чb++6G|-_F`{%r +́eF/;s狯-nE&IiFA$$ͦy̗m٦ΰ#-;&Lza/צjSh%bs]\G)%KyQXI55a{퇗^k׭5* &N,O[0 )"BGR)ٳdm|ͪ4VŭfVRUQ/?ݕfA [_еSNӉr^I ?n괪qo7y\O.h:D>ݴjq"ƩkEe.bj+yPi$^>p`g1wޣk:lVWvPuӛ^"2DVT0B=A&lٳf͛6lٳfȷbJմ< } eTS^yYѮum6mH<-&\>`s,(pMO ˂kx=M+^J [ktS!C7GG6v~\$7[G! EjDN.WWusioq%,*T$9fXߙWN3Y6n|D!R> C¿aYJKm k/1\/tH}-Xde@ ӓsQS՗^L4]oO,5Pz@r~QO,eo4izUDK;gQ>Ӂݔ]M ?^[.exnM'&Fߌ6lJc*1L;z7U5+5ƏsRA$$B8P?NU| Aa)qk%ˣYM( P_ֵ6CGS]Cv)BHU RBz\G^w򎝩~}==)a}mfJƜdvz$6vQiF^nE )'rK1l[7Pd]@DS[4>Cmy7_(MaoZ7I3^C t`ÆF^h4IH"%H d(U)VnUQFZ8"6^h\%0JM+6 @|Jt,4"{iՂ2 jzE 83Պ#4j af͑>h6o}^kY 2qo=GrMbw:\e@%$Jףltmz[Κrw}k0-!B#hGʽF˰h>څ9` o {Np(NG~`XYjiZΠFV . F~$^BRw6lٳf͛6lٳfכul4{vMȆRj)Yz}doiWk1j0$3Zd`9+G^Aj< öQ}cv/xz!F˪[%ƗAim)6hF\rt{zTfܳ4 cI[UbI놙c'$>pJ CK+|d|:֦RF[`Ees#|Sl}{-Ǘd6m_}b]ATZngn.~PkeFItGt1# 6bm=Yy@Kۍ'U-R )n) \<235 }vg;S^դlxX H15,ŷ'sf:Z=<[4LBjho"pf/)[Mi s(3~"*A㷆,[h<ͣrzerۧKD˯k-m5\Xi Yc)Ip9km _3iz-X.WrX]<'/!%!=dg[xI(D^*Bڸl.~)$vGkQ xZESw:}ŨfN$~RxZ .JrLa]^mSUik&jlVn!9_r+H%+6!a:Z01jﲞ#ԺƝj > HJ#feMK3f͑i^y-zcIK rKU)RhNe[s]"t5[jHJ- uu"Ϩ~&v-ټokF710tۭ1[ݷG>ܗv,ڋZךi־yOGF5Ԛݍ\KH%I%ZFI>P@d6lٳf͛6lٳf͛6lٳa󆖞r_)LũKfod`=Wyܩ7{&{+tDEљ(j×HƊ;#Lw#TKk#r.`A$:m7i5y|!##:׮-}t-,(#iLiNL T]re:tRAsmymuαUØԃð#%FZkGi  4$q, A`CHﵻĖzV5,6ѼAA|ѭn.X-Hy9ȥShF}}wO^UG^F.Pik ygɆKs*0Lu` OI]C,In/YXP9Iojvַ2kֆay̋n0$䳡N k^;{;dIP^+bI(-j V|Z~ffsyZdm!tIG<& O9-Ga<7RY]] sꞈD~?U%h@XajS&csaqo蔒h^R+?(+%cq\#ѵ/Ok+˝]m?M32$S.shjBIm/{\X$r49чc1ү'ṞY&4L@2^Yk~~`X)q~nZgŜvw&۔!lݽ#ἲ$FT7/4kgh崐1#cC+ɞ I33q TVԯ2֛'ǝZT%[JWn\~,厧Z>H1"Y\ [ai_kl`[b&4[1Y)śm|͗>vz^K}dD\z k IP 矚i$SL^xXboCO~#{KB2O}m%DdH]ѹkaWqpU/pFr *M=44Z>,m:S͜z]Y.F%)V/ĭ+l:wC4n#((E TnT f͛6lٳf͛6lٳf͛ ~s򎿫";=ON.+OZ'nct_\>?FEmYŵť\i,[Y]"%bޢzҸ3ZϘmdiuFK-6Yf@xdy`>+Vⷶ8\3%K-rwl?բ]*(ԚH$HZ)T7y~Y[}'Ot mOQ6v!6j-bBqx%@еmB{BkVӒ_O,SM+\es?;mfL(~#SܖK40$Uk-e7 )"Wm|yb/:ާ>>$8$̱oFmw'MosSiBSh$?vE h=GN/D'izl"kX)Dsy fhB!jMUg雞(ǟ`(lvUt]^^[ڊ fTޔisk0yF SMNex XS҃~2\6dzc1sX\7ߖ]jK8cʢc&hBY*hiL'妧/mƚu8`KJЃt@4oZm|;gJ5JQmnYKmxs[qz-B*{o^t?+O&\ɨȓR{Wxes=Mui]b/BfY ԢկU;M̈́m嶳\@}"ʀL-S6PitCH]I/@?e/u{ܑHmdHknD_odP?/l*:2ntQ{v$_ԞO鲭845CPӖ}ɒD6qG*T:23y$k>~E΁>mf!d g"HU~~Fly#U󝶿ih%ē|mgo_ME(EZ3f͛6lٳf͛6lٳf͛6l_WZ)j#iGsT-=Gƻkof}FIu޲dkρd6ROJ/2Z乿ՠ汼oD8KD(UndL̶Sv& %)`/jEe !^l/^dEqdbHP0/WMKѮF-2HX:qo~T)~ZӴ$ƃaSZulB)f>G̐H L7_ڄvBJٵmSQ9խ87`4cM.mR]fI=FkKXZ% IT恊Н0e{\ߍ:Ma`DfFinԏjaMuǼSQilsUm3kcm6^[\Qs^,kaw/'֯~VNCV}3$]d(É`mNaG4N HaXZ8',ByZd'':>{acsr.^M:KYb*n>G-nCJm?@hNk-Ei!U*ZڕO5,] >uVFzȼx! d7Nuv..i&Pm7qX$×OGz}~-ysրNBݧa--uhڴxxƥ#)-DTMuMd?ΞJ#1az94\ 'T˿Ÿ[ʛ鵷!/2m&V}oMwvZRNTu>WHIhvn"WW :j6@1km*y<Ӻ w͆W}͌ =@ \xe2G$+FHA:6lyZƋy=7wvrEw#Gq3HvFM~fR@QbiM>9`+TvB\2\ZfU }Hр ym#^]:zH&Y*;#O z+jkZE{iX]_[qEw s#5k^^Za?[sgnV!;@]Tu ͑/1I4"KK#-8ᨦy65b Uw]HRIRp;ZWuKlnd3aQ&h@xE $}Yߦ4Z^Ic3O=DcJJ$lW^+C<|b4]Y#䳆ZyY^_`+i>q|,l.L9G+œ"ìٲ!V>_+;9^ ZNVX=KV[L O6'${O=~\{߼(6dVQU_y]!M٦*^6!t 7ZqRqw.YWSR9KD׌R%IF f͛6lٳf͛6lٳf͛6l$XVaI;U33PTI\֗SVh$g*m*t฿8w[ҵP]!sN@,kaԾ|ғ\M%`V{Fx-ضVqʔsp^[SMTd$ d3q%7fݩ0>ɦ5oa{*5X"-ˁN&͛9<ݪo̷_ZW:S4BJHyp4luR{=*ݭ#Y'{s Ĉ[7n]m%剝/Jpzwp<;-Suv,-P9WQ- N뺑!7^/B}>U Se4q%f`6&vo-MVtl'T1! #͛ 6cKHΣ[WPd6Y3f+.jO}|i^X؈sĴRr#ʜAZd]?(]#o銯{a^ӉZzix^g̓Rkm4Km=>rG"paB{\=WTO\+^jAyoΧK?C`!6wSY?8[Gszu_ ٳf͛6lٳf͛6lٳf͛6l"׼WMspC4iM%! *BaSC | !$1Z;Hʈ#ka; 5ޕ ?͇~{~լ3EV0iR\5ܾLXLf -Efu ցL^4񥅴kzBCfYchC<%ՅӈX;^ 1,L۽Q0->*lٰcqx:jJ}qɌ / R0 _-Kc$SC M1CRј[ʃH,.j3Ysz[:CQ@tui]-}7xnQ!$/"Bm{ns7֖(Ll~N?-t Ԗ3-1ͧ\i2Nr grY⥫kLԿC,ך͌4 )b!q H)O(VNc\I%mD8GnlIoOoJK廝;Oq]ZM:DCdUd@@_WJх3J<1E#čC+esʭ^|>͉AKxȜ9!zuVYxid$R0𪎧˻K8V]6shïdq@$UD&g k/qUc[c0˝>=b}:O:]V6iH} B&(z<+G5Mi$KkWU+;ٳf͛6lٳf͛6lٳfS4?Vzj-$dZog$[F|$.OnR/?8.Gu kiwŘFaaEaϑP5тBͻ}OI7r7Zb{r~kjc-x'ѥH؁~iEeskbi}%3'"GDFvi>sӥd+0iP;T)UW`?W}OKI;xtFԸC3DA:*Ϳ،v:F^G;[yoȊIt %Y|wm S]]kQ73HhÆ_%ۡ0?4ӭ*I]tַ}Wd@9ޟHZ>umGXDWIAPү"O:o Ե[kJjwzP_T(f{%xncQu͡tnma`"Ija$KZzփIIR$$QUnU8Q-N+yz; {YGo^9,VoۮK-OY{[.JݛqȚJޙ~dIe^%\RRq[{^ G ByPUw9-LKY\B4л MmkQɨZ!zIEB.Tژ:_VFGӆٞ>.] jʻԜ(l4v; S/SSR(jbw( ڕz'Ҕ/дm{O1/pE.uykzMݼ&Kcd$UAl$]5ՕB }JjSZS"ߜ/4k˚YDm!ƑXQX~m'$w~WFa.,nA3xbC0ghC+"ֽ8#wW4In,-._vcThOZoFMuMSmSRkѕo&V>'!xcg]7:M.g{uK gg'n@e_ek)4KLSXn*"eQЦPv%͆>E!h'F$R 5W4ƥ4z?ԞPsE, )27kZ_5-'廫t aC\QaˊnrZtZs-^9 nVxfWĢdO=*VoQb}[(X#[W`j~ms1 ̏*TSb5>p]yq.ܭΎbܷs+ĤC^-Q\4|k@㴉5H-=$FOKC޴4̽V$B$HtynŸyo8kbOiZkr ~Q]I#3kbo_cYy!FtF*ܗ2:qGOOɯm=Csͭ 7W[$'YGyuB<.m08Gqp+ b31Eu[~aS5an4x]U3Q`7FAJʏWWb//1\39PѼ g5Wlg/|}F[pRݯtUw4!V>#յm5X#qyEi7[vh`۸r4*Fȗ?0n%YHOW׏VRNQR5}KNS8n"h*o"ITìٳf͛6lٳf͛6lٰ^^I\Zc Jܜ$jic$`i#t(DZ\41j1sn]jQ eӭӊٝ"("F|הa(p4չ}^ʵ&Ed!mr)*Jۨzy}+[k"^,x@_Z9E>6 ˚2Y٥ {Vu *!{"`>YH=rtb,V1Mʼx/Im";nՙ,9ѧye(1\us;m%y:7է!@TT5v/,W0p–p}5¸*|<Ư'&FIgG'T(oHrrp^yL}Q7_^}ߝSn?O_M|.'瓋O^H'P7KǓJk>Y X'%,跶P_wBno+V i/":L\7-9%ONKI%KkYw_Dž2kK[iep]H`pMVNI$nq2J* skMZ[Cd%}>\(\>OӴnmZ{:a7+=ʆh]f_Td{aG^GjX6iea7US~PloХ!Y~bHcn|_p@,>.lF#dDPƮEC9^@wjL֭Wbhl"a?JD䂛e,.W6j׫u vGQ?04R;&eYIe{Zsn2E*FK?,roI- ^膙~񜊖z?%j]kpNۛz+B8N?~Lqv@XF5՞5 O)-Է6HWSkjKA ƞ1*O'y}'n,YLZYdcm-7^Sd{+\KSJ&l#Q͕j~H֧I^ڴ5YQٞݓ/F4Mz/u\Q\4Oz$Ku^A퓬ٳf͛6lٳf͛6lٳf@׆\+$כV i%/M6 XJE1*AL$&Sn5Ku$0D8TQ_|C~-~|}ۚGJ}m~ѾoYB5ϦPZ'l /<-=iz0BjZ%+D5Z>wi%՜3I4e"޾9/压\[[ZzRM4=3Iqǜ/Ƶ>zmm_ƱEQAF%s$P;FTjFO+4Wvet+jpWJZ3B @pqNؤzֳGcd4K'*j{zwvkfcrR0f \mϕq$IjYEG $?U4~KӼqkm2 3!D|]ZmOuk[VH̆In>so8} k5,NO RpQn=cR;ӣYmP[ߪph,8!;]$&C'lVɕnZ # ,ZC@oQhH+\sYk+bFu $t ۯ\\)h%ITlJ0`>F=WKUY]|E1Dy}$52=(h( N7doO3AskkgZe; 3@]Cq/-/?=-ɥ:fQmq΋ 7W37"^(ƃ#)֊v8M2-?I]MN .SфA+)Kc (ޕh{М;X SWTM|L@[[B[ʓB$lH"♳f͛6lٲ7[ߓy:Z!u@uSPduڻͩr.nogtkZm'xD<խZ>p-/LIuP(10v9.4hSCk]"CkpD/hCFpjQz!WX"c K-\!ո ~ `77b}MK>=ªc j)vkv424KUhTpUMz`[+ _.gMroa{i BxPt?l[~}ϙ5CO'k)-F7h} *@G2[KRL3] A%v78 D)'k-۵^VF#yLAwne}PXF[Z[Rc@@7CïԫkIR<K{t GV{$Jp,:V|-KU-ёe=BYeu]4,]D)yS07( dyM"B=e[[%a [YҴZJYZW6ߘ>Z9I8ג!<-m8d8.T?YkS2|/_C[vʘ mFM ׶Kv_[WH)5y?Ґ~\ˇ*z-><6lٳg:tUF[*OnUqCEd_M䖨vX9uoIz!#$vۦw%mWѴmnHs4ܷI"D߻j['mgJ'a"X<3lZ0qj ٳg>3?5KG'Ϙg'<,iʔT#/.~f]%Zl{'X,c"?u{8_~yɺKVq$hDpɿ]"XgʶoN Y#ky%Zz5s[?3~A~hԵ=f^ + #LL?3I[~am[Kgѝɜއ`N=:W/?ɭ'ZNO*6qru*CҘA??>i^fvWy#!)9OCl3ߔ/-jii9h">K4HLy*a=?4>?-mwc յ>4 *-7 _~~y>d[Vo/^zvw"$0oL(?6sf͞Zy<%x';_ᦗaM![+!#rC"̿k?<>hi'Kg*2Ct?W1<;/,:j0ԤQeM…HD|'Ֆ"?:8rfWw`v·i/M{UV:[klOz0@̡d{zoto$9LͶ9+ВqWvVw,WMTQOL]G٤ǐf_)W|ߪiBQc,#YF֑̲ 2)k/&>f5[E"1!<wCMHDrB6$T'&?hy}߫I>6 Tu }Yߕ\?03!kk9yA4K?-?mѬK<6d14o-OQzɅs~^y#AM/k}Yw_][H RE)Lyκޝ=rI佽?%bJ'v;F ZYmR[k/[I6"t4;ߙ]2,+FJ̳͜AUkr_ѳ֙4r4j}6dk[ԗϚN6k;E%բ_J7T! SBy?Rt;[w2ORWCʭFWa50?4ho㡧o[_󎩦k;TtK440-);tZ֟hosK>qgk2ӧ&hn*sy IiW]kopi#UFf͛<m__ޫXifn.E-,)U dcSgޟP%PE[1դ >!|6~_'_

m6R;2bh|T 럝Xo֓,K+0mG}B pZ'?:KY-䂃c(V)lߓ:$yvtY$}izD5zш{a]j󒺻i"S`Gzw^[?3 K3[,8ruOUz~RXNmCS.r{*#Br:dmKu47;Di^| 2[˯Jz\MAxT*7>[Vz`/>ǨVEcywݫZXԏ(7d6l׼f=%Z/b;O#2U6;]s^GxK+H)G jpMl4l4t^[(誣`0NZo[PA YUdIy%8ZƮP~\->`&K/g$=%4"z ͜?O%=$_Pb'쁰mkq|EiQU<+4%_J򗗭:zFO/-G+5̖Z@F\v_?+4gOfdIu(ّQLexބlG`Q{w$Ksp](VBl;󧕿%%i.xg$S0~\/ct#U>+Or)ʽͿ^OW]π.^Bhx퐝[s{Z?/k􈇓'^le1-" /J<+|_5yGSRZyvo\}fvc,NQPCԞ΍9 ލUűO=9t)Yw;bw)y[״Uto44wZ$7ig"9P~5,;F"ɺko1{i-4%Lg~QTJ;ٳf͛$"-}(UOMg+$,JO.@,&&Ā`o4]^]iј`bG%;R ;7-<& PX㻿'xPGɢ" ͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳ/&][3V˹,#XB=0[\ɞӼXli^E }x>ȥObC 켁mB+7~e}MGmc LJ)TPamqr !u/۫XX՝% 6 bnƃ:p/ʏ7,bY>Ϥ*u8pCe"Ÿ06lٳf͛6lN"u( pp=Yr6ߣ_0Nlٳf͛6lٳf͑O=~iy#Ȧy؛URzSO//Eyԭ" ȲF"S6lٳf͛6l'|y,[I[tY?7򇕼\h3zpR\sO)?i)ǎ|0UMbV4ǥ6U3~Tm ml3iQZ]VYBe>t5u'巚Mژٮ}PYu,v-5'ߘUV(jeWCo$h~_ēiPȈ9ʴ]WLt˽2=[+^:UVTo*y:- JZOdf?eF{G6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf!ȫkC˾_ѿOykv)#u FOˣge]>Y m/S(-JW|KO-'t{[[iJF$|NV߶-_5;-t=Xda$FAIʒ) 25- ]kNכE6ҙ̂_/Kb56.MRyK;Ǥzr&hI$9䝵4M觭#T&ҿ";lٳf͛6lٳf͛6lٳf͛6lٳb7VFL$ACSoqV5̞wYIn!5?{?J3f͛6lٳf͛9g~uMKmfl_66OiH.~(4mj=BEkڧ:DaIUG瓜)-MM*Ol0R@f <2g(yy[?6z6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf2ihcz}4+\IdC=!q,j>Ri#rf'ڙhѬ&m}~[̾A5֣c l=Rū>e֣мkRfMR +L/7,35ie=E,!cS*ݙf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6s_0y{V̷ctiᑩqunH?w!|EM>Y/%\E iqqjʠ< \-󦡮yv*XG[Vg7?o\D%N$s5~cqZI2ir9,%2.ʇ%mw-rY6ז{F2|3&=حڜrȍ A*yZt?7H/=%m0)%EpnBlٳf͛6lٳf͛6lٳf͛ji٥/:v4{ג3+?1KUTwd=GZ,M$,֦i% x+N=fV0_~ey6h4H/a »fռy|{ѺvsDA*J!I#jU!*L9-E/[>h]H!S}@+\hP?wsL#V-2ٚHcs+6wFE%?%4$PyP6Vу,ĞyN]6Ji_yQ6lٳf͛6lɿ)HTxZdέ6lٳf͛6lٳceGg &NϞ͛6lO~zFz6lٳf?9,zVccipuHј?*fB;qJ}?O>:~ss׾`~wBJq{[X8yU$1;R+8橆%IVZ8ٵ]2FM$.I-D*!y _/_j6׷mUۑ&k06yKr'ճgsf͛6lٳf͛6lٳf{Ho{+{)=&$W~%ypIү_{?O׉$_^yN@6f͛6lٳf͛6lٳf͛6lٳ`w\4/KЅQY"4s/]L;ZErWѫP['X=,P\Y\ޝ{JWk)*áÌ*^]yuN\FE11VbE?-幸aIrUU[o.ym<_)~H] w)Fք=I-YRGh%"RE䦫QY$Iy0Q1aWwIM+b/?!͛6lٳf͛97?Iw{O8K@Lճf͛6lٳf͛6llݿx[yf͞R֢TV͛6l7 o3Zh7]SϨE8ӟ_}q-uՊ65ܴ~hnwGo-:ikw][BDHeP•XsKk:v꺌+)$π@Wc@xyKV/RtL$wȖEn5@ƿ7bGRRխH4qzzT|gN̗ZuJ]\+a`GYF:[cJre {6lٳf͛6lٳf͛6l>1?D瘿~ߜײ\ٳf͛6lٳf͛6lٳf͛6le P  ЊsޔZ6 E+7B2>i'}ͥw,r4nҽ7LvUM90EĿ1 ;*ݎmaln5K{Y#-mj 'I$Wg9u-K{GMsL֢i ?  Kk9)mv{yuל?8O2h_U }''}Ώ8SJ|9f͛6lٳfM9OG]^.>w?&ulٳf͛6lٳf͛/o?<8_)7>Vv|^lٳg"?53չf͛6y'>J[G}O?y9Ie+k `ܜj4%>Xכ@5ZdڄqM:Oc:Z*=#,K+NDSe @ __og3g[ڡUPA:zU/(C¹#<~]Ap)ld^5;?-uG4Fqy${9#<V_Ue#'.chZEzvZ|['R#B-}0M͵ͼ1,)IaC# e;Fyr+@_"At}M$YG"(&=y6lyXWZ66`(H" m wȗ<{tjԭQEQ-F!^ʥNzW'^Q쵍7:z$}nXzX)1oݷ.9 5sZMoDMam18-N2S vb-ݍK̢&I iUIe]zXv%э1 ]+|],//O6޿hqݥ,5M ep &'CB mkVuo}Yu+#hnFNX-)ʇ ̲i6%b!-9 0\ G%^O96Iu)4/N-п'QG`TMrK0!5a[m7qo+C*͛?ϹO9/?~z6lٳf͛6lٳf͛6lٳf͛6y'_o0WgHnm#'sjG'Ȋ z4g,ݕٖ:p4ZmO `^Ko0O5}P\%%A!2 WƇCs Y.n#h̐G#j§"VlOcўXF֍+~۩"s'\[͚WZV]8-abaؙ$nn)g9'K Ji_yQ 51Z*YF[c閒kV.(-r\OJfco6&ܶ󾝫Ioo4D*Ř]s5-FMv^W B@~@afO/jSv<4)a{Lt2`?7Y{9-fFM!j_/Zvo#-Lf`\B f́'_?=K6lٳf͑?̝˩kOqh j#Ug"Gd|:l\[;?|a,ib+=J/ZH"`~9͛6lٳf͛6l$nV6e=݋H흩,fdy>UX֯"TV9gS#׉lk/<_5 I帼mV]IUcHuZ8~fOS-4rck L!WҠ{a b}H)%XPE|!i˖Ԯ)yJ֥2}dS717 G(٣z.>} s??^h0LXU8SJ|9󎑫v?PӤB.'2(81PpGOl}9"oLK"/i]=>yXJ#f/?Kd3G}.]GR~krݣ 鲸b-Rۍ |~R16gyoizx$2kQ"Fr܌4<%:Uߓ#eXTPqɸzbo;0SQXvfTyeh$YEiեWpIp*U{+N2[[,B^& Ӏ~7򯙦Qt{Iqjs7 ۩[ތF:ӐA<,.M֢6Lϧ\G5bSRUsM[k]N$Ilu`2"឴֛g>3/cOЌ@s??o{ƿe\"hm"F&q<9(?S~iuq, >8F͕/td`8:ӑEj),t󍶓Na{nY QUPgM篒|ѤsU䷺ȌڽvяR_Ds-=Co*iz7W3rbkQf VΙ6l>wп ^4G"9ҍ-O6׊^ZJ.aT"DnG(ZXI (wɍ6ѬVC*"*x)甿(yy[?6z{jb.)cAA;/YoGdQwK[cˏ/%5ɵ?co.tħTa<|}+9t\Cj#8TQ+SL=䯐UϝJBM.8(a: Iqǿ, 6JhŸߔ`:l-/KZ>G8n}C;V/>XgZ-Ԅoqfe m $gHB6zO6lٳg|9IsSviZ^x*#*-c#4 wQ4r]C+dIY!w\?ԿZf͛6lٳf͛6S,ᲇG 뤷nA8)|1l󦻦[~jt[{Lnɫ\^]E5tB)J mКѴM=ѣ6ЛhՖ3चdSXEΡ͋C=^ut &Wh6~ku0ūpⷋӵtV`Ļl;~ZGѵnV~"]@ h=5(׮N:1Z=ЌCV 1r.ؖ$`I3IGab¯W^Ca>I~GsUӼ=jV*!&yU :Ya~S56hc1bzg:~?X.>\sDnj Zg!ROS|C!Z'$(YX$h ;U@$aO ˥mמ]jWm'QĦhY/L+L?d_%t/;3˿?>|m g|ٲͿ˹g9Jj&a^\Դ++mNKYeR Ew3_?^濖c{w=->q1O\ÊQQ=qOK~Z7fwsw %)Elٳg8/`}o\_@jxNro$9~`y6ceO2wI?t#a|p{͞4)-]'ԭ>2Q0[/-@<&pua} ͞ro|࿗w:~sBK4EK֍}A(ÎRf1n)6&~&UA|?<@nu_6v႙$zOASH皼Mb?0ɩIF3Sp2]6lG6j6"_gW_xDSl4~Zt]aMYI@OiF'~5|Ǖzr8ou?'kq%<yMkGnuk!)ʍ=x"l.ZZʃzTbiol粺KksJDfI<"2T3ܑQqHDQ@)9E?PLnqkrG/[%l Fy~_A~__sދ@#NC:^lSayʶK;G!i]bC57?M'L]S붱z^(n5Z}ZO3o0꾠ӴihdqZz_S:wy˱yC,DXOMD[6l/zggM̩ $ҰDP!]ٚ :y;w%5痿.5"O2_[a#;W$'=Oi-^-esp 7HASEV$lٳf>r~cyf娯tKHaܔnR!X -&3O+6v:7Lj; 2ٳf5u剓WӑKtnW&Gߍv=3ZGމt6[`[y˸ڀί1kwִ:Dab3U2D>ݶ̏D󕗔n?K_C--踃Ӏ޵6ZJԭ4P/cx4@_B &s#FZݍ 0_5THiOD[׭`Ͷ:aizmA*8&)T#q"A3IGab¯W^CaI6>O28{yu;~yKZ=/_=[[ұ本8U _Gα8M8qw.PV6ZUmtjk_8SܪXGiv1H!u@ + yI蟗Z?PXg{d"'9/Xh隅w܈Dx:őS9ӿJ?wQg"|{$Ϡٳd/%/s&s՟LÝ<9#OQ͛6'q:[<374QSL8U?&?8|h?YEǍwo/ן&s_ïH|g-V_Asg68/p_b"]oNOpaMmcZw\cs?V ۈڦs~rϘ4srl4 'ǂj><4-^|ܘ,k8~# 3Wl8?(ߚ?2M6z_6lz|7 "Ut4i"vmD6kgm?KӚ8-FHLXq:1D-/.V{.I/V[%OAyn5k^Nc$)c%:AߋQ!.m}v[}xMn&5E3MYTRY.c-lXU?% a{-j45rvە57 ~`_YğWrk:omsfML s_I*gSA㞱?4Ϣ4޵l4"-źoNr\=X{h-n%$oIŌԴGMӽ$BM Rz_?]ƙ$RK5n\B̬-U4滙-2{ ƗRD>!ZV_|0_\jWK,OX|S\)գAa[g|y[M6ޅFuB%HAPջcKR>HӆG"ـ/!yY4~Y:,Qjk0pId5٤뗚m޵[I-Fׁe<ҽ8}qq{[{Jzzan܁Ou_:iy9gO'i>D_t[{gP#k˸֒9d1}@˔~Z8.|0F Nr!Psy~erh~W;3&f2^U|_6sɷ~Yqu8PЬ-nsn@Y1-?@}#rThl|9k0켟]}џ:.^Uaq3FM*~m|'m)wND*v޸/dhB趑5wM2yā2]ѿ/WU~6ԡN 2emSZ 4k,m,L*zJsleo&/X&辊뜂)ET_l6踞/&r2$륤ʦZqoA3w~|˶io0hTrC]<_r-cU~핑)g:]mum3S)' REkА~󗘿8,5l$Flm=F=CIo6蚐;K{V(*`I$S!ڟ? QNN-rZ.Xr<_t%t:ϻpѧ';SeyBMorJ?'Sr2+ +qGYk>n>zjXxn>A1?0?0_3XֺttNԒ8*^ag~WiXCoji*9q +sYzעkC EyX7.-=e-C)M,{-7to?Qd~2k-hRzLemoJ}4P9bru94h?>]⹕#V7R ҿNpVg2f=A1ɱguKbQm-x࿎IMri:ծyu7yEեY1sZ|~i?,ag4 O=.Ab'Oomo[tQwsjviK J8<ޝ89Ll.廗SDq|Q:ϖ5};IvujbXu"R@Xr{Zߒ.Kx'8${g+_п/4Ȃu5!dvƙ)V-cBK0Ium9KMD~,~c~yma@[eR@n'I"Ye[h݊DnfռmV{Vg. I"Cv 5\Ĭ^3g(y[?6z[?Ϻ-:-Xβ7H&fJ3i:-%oTXJ&b WsR,E)_{q$vn̿?Ϝ'ח:5.}́=NKӮu-BuR4 -9s2T^^0>9'6o5Vtuo}Iㅝϯv'$ Q\~L< V*i_WߔZU=Σo5j++) PM/eZɱ<ٳ?]Cl&?oikЭ ]`OVVVR(Al=#au5yZ4TwdEP~Ny{r/V徉y[-ؚ^F%QӍO GT6?ս;GMrSpP0M??k3 ߙ?КO&}͛6y?Tٵ;8.SAJo54Vh0~<ڟ<ΟG=CW>zQ!VpH~#>G󮄚om%*Gs o+^;'vCZ\zmrGU;!6lB;xcF*+` /4 Eͷ꿗dq^>`^{q.)7ZEF qF""-@7cS$Iy0Q1aWwIM+b/?!9(2M.pW7^OC? ?[tdM Iq{ws,TG3˞GeZɡLCPz6<}.k24i* FT#-PyuUգ3\/Γ8{'\14zԚJ\?>|m glD1ɜk{-\;zb<#~Gku-̑0T@w[鳖Lп/Ϡ_mP8/1\.Z80mi_ܶϢx3Y䠗6pQ4ell?ZtMfΓy9VglnZ`cRUtlv1o94Ѡm=MaxXkːΝ9澿w8|o-ꩦ7&s+Í=,y_c2[8n/ciwA P^ s/m(i`/@ݣ-ű<شCLmZZQadi$TE#$A-2Dy#RY'Xh7MY o])o5]Tӥ5Jѯtׁ))&M;JIGab¯W^C#sQ+e\~.&_S$|TӶm+]day("$`S铯ƍr@߮[[ˍ7@+SP$h戄jw9~g7\hVdfOe!˕0#UumOIDZ۩Uw~ n/O~PU4Ÿ7'lKu M F*0NcGink|`oS|B` 9"Ia63_.sn-c?>|m glD1ɜ痿_j"?8O1\ɡ=f8iHXaRF9,vsp\hWGt& ȵ6Ξ`hc@iބQG̖fƗ H+}R;⒜HiTl, 0TSVѻ<`9oևѺ&zG/zlMBs3ּ3C9oO ڲ <9(?M,4-zR7dR[~ aV閞j'W`Æ3yR+-#X֭] 7HF>|19i_h/G<1ig0aϜwoqic5E}I/8AhC#):ƶ<ѨG},1ޛ{tX!7u~oWZ9<ą$ :液NSjL88UXo72}%Y,moa) moCqF;~Z=[  PzV2ɯE|)u+Y y!N\Is~yWTZjb{;+!~gخ{c?Ϻ-;,*1Kοs3IZ\ޝy;qotm߮foOk)PMyCoׂͣz"[3!Q1\?z2ק}͐OmtYkYYJFhJsldzPI%+KSƂ=_rSV0Ki(}8ֻ*"~`O8Ԧo3u G89~cZRmF;6vY4 x5ξ~<F6lQӬu+/[;1 Vyz\jh~jִ[AΎ= jz#~M#M""[FjQ73g1ҡ5o+eĚ{YYln^EvU|wCW6l}>o8\&'K}v(RN?1CX{ȒSUbi$3?:oo2EtG ~v8EN)ED>B?8?\ɥ/h]ڬ]yRoϒ$B&05e=ɼNxs$Qsԟ(l_42i>nOZ 2RH8o4?՗gI_.*\釡՞hK>f6o%L<Qow@3 ؄wzP\BI+) =t~^3B򖃤iqh嚴zԳ3|H)Ÿ?$W>p켷&k=,QOYוdg=g"OGٰfϟ?׿>cg[H$; j4+{C=}:0jҕͫh:"7c)^<7IMk9>w[鳖Lп/Ϡ_mP{Nayl{4vUbE+t< VCP~jhļ"ZTQ oDg8J kG[ɦLf͜:ߜ?|p"w*@Z8.QRO*@'^v=K̞sOuGylnR3H2s ǗLiR&CZR9VViF AĒo0flO/ guKyQs_eoQ)9n}/\I.qQ2gI՞MKA3d$/~Rjau~GZ|aw2:?巒_o*yLӅO~շw(; G姒t,ND7wօOQgE"CЏL lGv0r<6Q/Fb\72?{Wi~[DPG׍i8/i>bд]nZuҭ9Ga(s_-ߒ./$L^T<)hگد/Hi"ǔsSq$կv_ɃOMYdEpBgk㗬yi3̞^k#S{_/AQ|Lb}WL^_Թ_Z^3zgmQ-Asf͛<+"O4j&>]G^әŗ7Gڣڹ([.Z[#K[O*zW&X/]>Sμ 2*{J^_+)`7ɬ/5z]rON#UE'DoV&Y[\JӼ6AD[@MARi$`q;$1sq&8e_G`ko?{<{9KTz\'J?(*M aOֿL|/w_zp6o%L4m{J}4o%}8%n;`!kUbS\N>,k(N7on[Rl֊7O?OtofęȿQl?'YO3jɨ_gkgƹo/ן&s_ïH|g-V_Asg68/p3ErR:9M+ۖBO^q?F>7M͛8俗; ufieu‰('bw_gAo^yti'|0O5"͚ǭŏ.R^m7:ŝ#xۥU;qa7OI1Oe_&<}8E(SayZ'<P缳]ɸ{8jcnc;Nl/oM[?d'qMGa?4GҀ8c(O?3y̟h]S'>fo+5)d ?Mk&1_L^_Թ_Z^3zgmQ-Asf͑9֟kaϪWZ[sVVWoL|FFi &)t#=#<9*5!CKOUm[V@?xykbgysY?[bY=D5k116xs7&`eysQ7a j?Oga1'O03y̟hMS'>o+24mXiaM@fI!^Aͪo_0}TR|>?Zϗ@B`KpnTuT*2Ng^O1֋?#ol 6lyʗ^e>߶ZM ]C^ vd`{9?AQG5CI4)Pլ5̶gVuڼV, x[Fž Q [6r/̫ 5OΟ:{m,C\[<閽!@#&߭3`OO.nu5zĩ^ 3>lg^[p˿G缟rN:~Pɽr;o1^Gtg|P;o=/?͇d6|nhnoy?[{V[cչTˑ+f]lZn`ar*{ g7IMk9>w[鳖Lп/Ϡ_g8/p3ErR:9M+ۖBOsY䡗6pQ4ellͼCa)X m<$ QɊ|'|7-/l!qkߔ^cP6l͛<9C?AqG\}lg)T__uiK=c8_˿L_?g }y{cR\=gK3ؼs)Od_v>f<-7չ4'h(#*y_Z'eE{Y$lr^#=#<9*5!COOUm[V@?xykbgysY?WbY=D5k116xs7&`foEj?Oga1'O03y̟hMS'>o+5v $T}{+2`U =I|3&?2Ng^O1֋?#ol 6l~h˰f;mn!kT$K?W+L@k?Z`(e;%ܺzo4I#G7/ 5-0pzVn-&Fhd2E,e]Wn;ʺZ+[j#b58ӼB˱zmмsq۰V9Y;hRVr)IGab¯W^C#sQ+e\⟗/fa;5X[̏_%?QCVhd |(0_e7)?9rs%|sVxC''ϗ/BL<9(>_37Q'\9M&ȴpA>n'*{p[yC(^D.ֲ({.r_ovLՆvYY<|GƎfȿQl?'YN3jɨUAO2*}Z/v#~tZ~Ky<]iR[RL~y+־sO?λ˝K^ҥWXHX~nY^0e^"}I w5vBg6Cp_˟?gusZW-)s脟mg8J ?kG[ɦLf͜WrZo_IxjvPpB/jՍ::ĺ[2 ЈlG d%#4mf7cQռmJy"bnZi9'@fج>y󦙫.{=?N Or"Wm#ѩyO%77-kI#꠷J˭ǡywS֤Κmm (\'i$o淓[]:M5,he,~rUo8#>L|//G:s%ko/n?&L/S>1ɩs&l~{oo?nskA'Mڟ>'埕dOyK.LĘI%jr9gߕImg~cj"CЏL lGv0r<Q-?W7oYxyg4oqdq$կv_ɃOM˟@dKQ%?-pP0M?gߙ?КO&}͈W'>k#S{_/Ag?ytKU5eμm~c<F6lٳii+_cUдB4}.Gixu "YJ|'65+=3O;kuJ*f&S@too˝oΚSHrބQv]覛W ;k6h|{[{k~[.[Fr-VOS:WCl$aq;$1sq&8e_G??~,xs#&.lOO~PU4Ÿ7'l})$Ou~gy'\gI_.*\釡՞hK>f6o%Lw{$y7-)scgZ'=1?͇d6|O5Kr J窿lln%[CqKi%+r i0hziH9pٟAg68/p3ErR:9M+ۖBO3cr%ѵOc-gfk]GI4"gyn#$L'`6Zk*k|of-4a:"H3y#Qu!YEasc1u'F8Y*u4;lOyR-P.,8~fHpun* oLszike"tb,c0etѐLЃ^yU|];CfԞTsq#M/ʳ%rEr7] ]>Q[Ek 6d0Oȩ z{?Ϻ-;,*1Kοw3IZ?Kw[:STO/tj\ 'lx;7u?A0lGK)*M *"!?hG&zG6y#s;~Tk9C|(<P缳ɸ{8jcnc;Nl/oM[?d'oEA(8c(O?`gߙ?КO&}͈W'>k#S{_/Ag?ytKU5eμm~c<F6lR{e.pd6EV&,籒A0I d5/ʠ ?W;=Y[K [K4i$F̠jwRhqlyJ}˱-jD\Hb_ &GO8Ǝ-l<>$,-OռU('Fu_nOZ 2RH9OVOֹ]]TC?9mi|࿗?H6n[R ?oy?-?PKm_E8?(?2M6zc6lߚ:.ys\Ҵ#RI5ⷊ @%IyjUkI^мkg\wrm3Ov."0* Mk_(]rhVՌ5t#iԯ0ܪ;'V_u {\"ʟhGs`ee "/<9C?AqG\}lg)T__uiK=c8_˿L_?g }y{cR\=gK3ؼs)Og?*?XyOVhg=Q-ܸpQ1B?039?]?D_N67oYxyg4oqdq$կv_ɃOMG 0KQ%?-pP0M?gߙ?КO&}͈W'>k#S{_/Ads?ח.z[qW$֟1s:}^Kg\ٳf$y]k^`0;iӌI3~ @Ux_u`+HfIf4Ii].M[U6fҪkC>` vkrO$? 'ҿ"!y_c.?q4 (aOŞd=I)ʵC&SD-9/$1IΣ/4dkl+ߕEK0?<З!&}͞lK/w(.IQ7on[Rm9/NOe?&zc/$l9j<?5X2%Du19miCp_˟?gusZW-)s脟7(%|"oo&=16rΟ0FPX4|ןQY^x50?Q۰9 տ,./Ve$bYA?`&xa"̂E+v[}O*h^];kKtTės"2݇|Mq~q~d~Q4Zt~i 2{JV;jwߕz]Hҝ> XL[P2w-j@uѥMXҜaB-vxkIn\Xe5rPoz QqG\}lg)T__uiK=a8_˿L_?g }y{cRL=gK3ټs)Og?*?XyOVhg=Q-ܸpQ1B?039?]?D_&|eGd q'&=o*MœOVwsg3j&=6W?//FvB|m4q~dBjO<6#{\7M$ɜs?ח.z_qW$֟1s:}^Kg\ٳf<뿟7]|a6Wr6838jP;}'N\ o=_NFPY?؝NlyrM㳂VFTԖI D8dg&iWѪO-s7M^[ٱS2+V~p˾g6?-&6Ewl$֬澛c铬$aq;$1sq&8e_G`ko?{<{9KTz\'J?(*M aOֿL|?'G:@3Փzq$~W?.tD%IAg?7&s];=Kqgz@?Ƨ%ws%?wQ/Lu~Lп/Ϡ_mP8")s{&֕mo\!'?8J kG[ɦK͜ceޑ 1w}RH#dgh$N§]]?˖Ps 7zj-F]>(RHwro!} -O+l6>_|.}gP^:DHJDSw;K״7jd̶m~+]N tUmƯʈ^=AFwO(X?z%Ydc$ Ӷ[sJ%E (UAE;<am'HbHUr!h3ԞqG\}lg)T__uiK=c8_˿L_TO/tj\ 'lx;7u?A0lGK)*M *"!?hG&zG6y#s;~Tk9C|(7<P缳]ɸ{8jcnc;Nl/oM[?d'oEA(8c(O?`gߙ?КO&}͈W'>k#S{_/Ag?ytKU5eμm~c<F6lٳk?6/0^'".hvtuV'D(bԡ{gqgӭn.$NFPY?ؓL#q KX5cӠ- cN@܁B'?,jPyTu&Yi~]An ZP2A֏̟?ͤȷiWsFy*ZE:z_g?&-2]'[hY҈B\%4GWˏ4?/_'/2=Xw8k)lg3ǿ1teG'R~JɦQ=k`.goI#Rs ??Y?Z??JwsQRL=OO/B_6ys{Q/-|g8oOԹ'Fs(ѿoQKC琿3?:??ȿQl?'YO3jɨ[OW|s%?wQ/Lu~Lп/Ϡ_mP8")s{&֕mo\!'?8J kG[ɦLf͜?Qյ;k^sUiwLR˨$i@aS<(yf,[FD[yIPF%Տl<͛#:'۫[%uӄm]CIٹq*>._oUeu2XB^yKr'ճg(l2R>7?ԗzqI߳qQ2gIun'g!?}y{cRL=gK3ټsPg(Og?*XyOcO43^?*"!?hG&zG6y#s;~Tk9C_|O-L.{ϋxw#BE?ҮY=D5k116xs7&`foEAj?Og`0'ON-sߙ?кO&}͈W'>ly#S{_/AP?gK*&V<F6lٳXy63T5-;RM;TP"ڤGr\W+wgҩU4)jͅڟJU)V2++i&DvyI) R`A4ͦhz6%eMx.Dt- $Iy0Q1aWwIM+b/?!9(2M.qOG3I0̿j?V-Y GL]/QsԿ(l_42i>nOZ 2RH9OVOֹ]]TC?9miCp_˟?gusZW-)s脟7(%|"oo&=16q,nfMF[yn52HتE; \Vys-BA{m Iv'K 5:o" ,PVC& t^ @ Iʵ]`_liNν(o4=fBmnZJGaK+(k[Aq"XU \Gr&|_L/?^l5 >F8粺(yqUoC%9 R }Յo64iWnhƩ!+n?u//!kyHJ,+ggen8Gir4L#8_w nbyKK )~ihiZ =bZq T"07宙}Ne/ TEjdR֧,mC3&9;,'>omc\w6PϕUer}oei:ϔ._MH7jJU.a"6Yضa5O[]* ~fHNӼ_Ei&g} -1Ȅ WUlH/ȟ~酚ޕϯGzݏ5(%[o&XyiC>W˺W渴Y&^9JjGTSýWrH&ռm+pKKU K9/94I4>HY"C"X_2e!A4.51|J+dXlnFgkW=/.m$h-%w_KȽ+Z yGz&աA%g6 Ԗ+Xo!Vp)ɂ(~JZԮu _Y2*/;_ /HVto_?j7_c+/RbF $e_vq(E3f͜X@u[AN3Ӧ0Wg7i={{b%d7s#>Zִ-ǣzwpҥP\DtI^ys^Yּ}ZQ+ZT9TJFj >B,-N{sTЅބkEGt1?@wk榓w,zF.T,v y?'#;6^yWr\u:h71$TUiPz#cϾG4ktRh%$FuefLe~]ϥmכVWLW&y;O1Y\Eug-4W0MUԐF)1l1?B1-.~y㛏`ԯV?9yCMѬr72[\Ȫ*3OMdVxQobS井"U<؅~Y_3_o5wS>I^pO5cZn3E;[e_A"SK=Q?NjބkE?b\h7VhRJlͼ;0\,[޹Gi}O~A5#w5Oʩ-4j8)dxAi֋2GjzswDS `#`JezGL󷓵KIJ5 )mos 0QV!4lٳf͐_[g0;*ݢPрZ;KhktXEUP<pZ?5JT{[Fˈ%y"׃|;͛6lٳa&(yzCtkh6-s\;͛6lٰ_<u\>k[+ZVievv -kEQӮ ͛6lٰ~P򿙭mA!5QCt4;[k{[hmmXmEQQqUQ)f͛6lI̱h *_TX\It~Xw6lٳf=+O5gL,k[%Idq§3d3k/SHlۘյ mj$<HD!A2?/([FHJN,EW~qk-:HO2E˗ГyoTГyoTГyoTГyoTГyoTГyoTГyoT%FN|~nJMFTIT<{mTГyoTГyoTГyoTГyoTГyoTГyoTГ~_UD8aKj)o/?sXJpz$\G4o Uoo Uoo Uoo Uoo Uoo Uoo UgߘOYL-*z޷VE#e;Tң ж>aokN ߤ"56xpdYIuF+Bl.\RͪhDޛ߲]Ķ&AӤeƴF[ۓ!TMB"V u:{?##z]]+Hs]qb!N%q5geRƾ'bWiҤcG P"+aa\ͦy2G6Y/,X#ьTB*+I$lp>~^ZzQJٍ$%Id<W5-t MF$(u -F+Ju(MlC$g+x幱5+_6"]IJZȲ}^徳rM~үӿ/$mf_Y07f7+c-X6XOl̈́omu]xRY&URQ]]7}}*kD-]^y{PCy3Hh!9J8O2rEyekeesHnbx̴w~" ˟̭66=3PCo BF Z Ż*Ė1H:2:V͛ .|mtio^3Eo@ڴLb˘<+\BζQk-:Of.H+6ܬP Kf\:V$Q<{h)VʥOf5~b~WkzI<ʃM%`Hsߊ=}'ΖZ+^XݘѮͺ8䈆cUµ4l؅-%e1-D/9 Q4=,h)5O5lUUi6#j0Mלa-.tShF%0RIFԞ.4YY*cpl }Hfap\EX*’HU8T [+i.a[{H1pUjG5^@+ٳf͛6lٳf͍8䍣CૣAb=F+hН*Β4fʗiU R/04Mm@!x$*!<_=(kxЏ!ƣס`t;{mĶvƲTQc֘;6l]#J=F[8$xEvѩTB#5ǡMwi( +Z% QVal؝ŵͼ1$)IaC# e5?%z|eXZJaɢ^C|051V@v>iu=խ\3r]޸O*ybKWH{IK%[cgZbxWlvj}VvRF *78#6l iZfq"YY^@ƾ=7cn׶[uNJDol}b@f>ߩA^дXanymH"48AKlnEzpzIyqNJxAʪ@ lٳf͛6lٳf͛6A?0q ==il[Dl3W%k  8E;eQl._][Lt"xfX>6 zWoV{/rJ),g %&ߵ~xEmm>vMmɨYpΟ$Y^_$RGn,fGi8zօ|#sf:̷qذ{9Vg`>P>Oޘ s=Z{iyKǮ2jJoָw{WeoD36|n{o%V@/)VcOkKmukX.tK9)YMd#%ӎգ1-?s<R& ]kbVG[|zȶ, k [FC$d(PB3fȞگtt[o1\I Y!6vrƠ:>i;O/=Au[O jћ(00`iJG4fa;8?[?]23~Yy//,w uhV0Ǧj Vy@*Uel"O~SGp^֡{˦IGD())]]C *A9u]7̚kguksOnbdHE*SMM)/;2XZHWi=xݧ75)-Mfk{Κo㸑4:'-7Wᓧ+g*xȦx]Oh0MGdy%”40ĮjԯL=ѴTwsH[(W.:O f< $EM98zON]ёU ,F@CѸJԍվmqcsjvW=GI1F-fЇZR; fOk߬ش]Yyz)YaԭcjO䍖jt ,f5jB֮绰RGGj[I$ T輫Ny_ylLoY6k,2DK4,; JW$r7$yhYhl}67aF9+?<ӯE][Oտ;HPMmsPX 7E`s6P{c,Oi 5"v^Zo|82"5jn ~Io^kT9IZMή"bjaS󾯩]KghWi4Q0l5?xdjrޣl 95}VmfV+"2ג[}8VV${k"?. 591.^$I+߉alٳf͛6lٳf͛6lٳ`{: ?Y+D. ;(JwfͣN,Z[9V ]I|^A;fK~ĪTp#aXRLc$kDAŕFSEޑia%[{dc@( >v2{_.t_738Ӽz}6S╯ZAf}w+>}V#n.0Ŷ*Ok&4I6"$:Cm:<-]2Ki$I0icթfO'leדwpifOVIU^{#|1^Y}2ߝF V1ƥ@˷mj=ZS20fAAZ+Jӿ\J)~kkP_߁@fzj6V'u*=9(n7QPđDQX@U@J[k[y0R<. sf͛6lٳf͛6lٳf͛6lNۃqAJM|qe[h!U;iHpZ2yr&%'_*ys>Zҵ(ﭶRؙQ̖[-**0ʟK B{M&N;t]:#ȾC-)O:V^_6-nMt^9/HmA/z|52wq.q 9m$JH}?-e_)鍢jZiH  3 &NkPAΥ!~U/լb PVAki(%ed7_ymqs_OK"Xq_[%}OG3򗙼\5^kik$14QbTKTPmKhVzw1o$)X8yI(Z%[r91F,Jz94ٿDZRKӯgl+H $u;h,t}2as-޺ ix#9 נɦc9}<^E+kk:&hʱOޤd*O^jmOsܺaʹsC >&fpU)5.Y:.'׬omeҚH+yq=챧)aoM=p>fOayeI#2PP|ASv¯MS8-wF9&H b]`2782KQSӵ-uM톏=mi(^n[㢊}8HZIIJsA(ګZY{[:}aԿIh6H죷 ]\_P<\F,jSη|^lcAZZQFOsf͛6lٳf͛6lٳf͛ |޺SXM54>:Tr=njn.|]7g׃Ҟ) 7ܣDi22 ԚlSM;NԖQOjio3%2xu=2Ay?0ivz+-um3ђH{K{dlmw7:_IG%ԗ ;v0dlHo|_̞`/"o,5+tbOicG,%y|49. /fQ}FOQ $&H#nI 'w뒌Sk+m8i-0Z]ɎgF _95·4 /tҷ4-a^G4_.$S፼i[ cT:Mxإ+zF I^p_-+NE.?WZDD [+ֻoP{D.wiћ[JM(J౻Ƭ6RFj}\+嫍/N+GOIhe3Z$jL"l\(-u2Xmeqsr7eȏ#|&s+<.#0u]\k:dkG!H."֍,uW2"X#.!|&=VYa˷k5ܾ(|3o8;gg ^Xn궱~뇨V߭h\:ϗ.7[iWk\٫$6\InB?Cqޘ65^}^h-!ԐG9{9,ӶEˆ,\xO6lyݦ,]#XZHW<8dhhB܃~h_յHu[)k-LDY.E_ d$OF87y=VA]gJZ޻(Y,V)Fr~Ck:yn {]Egs1ƃl[He_Z)#V`kH5{o͛6lٳf͛6lٳf͛6lٲ/^{Rx"īy$}Y^hArOZ6'3죒L6zw_JCpzIXwyzVv:s8$m}EZhb2Kp0ݩˏ^ޘK|Z/[dBFyVݟWs\F^gBuo s[1UTH9^%ZzaXd0A805`ђHRX$kʐKJ5@'õ(0s /6y {͛6lٳf͛6lٳf͛6lٲs]euw,W7M]NmhpTyvޣ?ٮ042mjvQ閖֚UȹUe 3զ ic]_꺗D< SS!ozdʾa+oh7o:Gi/d:Iv'(;ւC'/ofpMI˵ėJVSE<Oo(١4hn{;fl[ 徳67QZ5֖@b[Y8E,DDٳ^}ռV[}ZV4XUVg+#N=p6_yz{7izܪE[][54L[!Ǐ6zS^oRM6 fDKyfIfVgs/<7//EG~Sϕ|Y+kSgf{5Dw_X+iXeڔ2}oαT[hmg_J)$i :LӠ*@ '2Y=+XuX-!mV6 ?I`y ^--Ξfch;[Dg\kF Z:HܴuR;vC~`:&kssK7JVמK3ˈOӋi:jVm$X"z?Y>ʃ͍M6+]:0GOoVFdFYwOp]~K5mc[SoIv󣺆2RH|{> $ZsRNn \]=>v44yKK-nYFRiBCqkmQU?=pڛoZ^2C4/%`јԿڔʅ/.5 /![h"kظ@@Ɏ>F7Y5?)^hֻԓC+U'Gtyu42)i=JRKYde˷#ר\V/j0ht]%Y!V[2nWϫt;a~H}yQ[]bTVYԞ ,MPȨA8#}J~][ӣ,b!/C ><( ӾH{UcoKK'@YDQդX6ǨZC͕Rikso33K0Cekp~c-/c7"K2ƒ`>l/|$f>+'O,~Iz<xDLc2[yRf㺚)ot]`27qqKW-X!" 4(E A뼰95[1qѸQPf~⺊7plRٔfkh+ {gf͛6lٳf͛6lٳf͛6lCPX.dH"vYX)!zg=nt=6~Q:I<1TVZ܎鎼ɶ+K[abPW-ʹhÐ'nJ'0L is1Ԭ/4JUu+kUŴnoӣw-y"K$%WW)k˞,]>9ۍ:Y.[G6y) Jy9tM6nD߼ڜ(ʥJoOzzGSIkD0> KSeΝ,I=ҫ.Tz~6зwkER\ʇGL x /*:eY!#h9/F oO/Sltt˨\_N[ eby$$2;`{oZ<7 L I۬ÉjҬnᕟDW"MM^oiHԧ} TگmNǁ]SZAK"ͨM4!PMuRtDںN[з>DXQVݺa1[Uiu/6t aуIoATZw/yMfMRjme'[fd% *ޣ <-ۨZϪ˫ k$Ćs(LJ1Q7"iܑii(e#>0i:gC6TFqaw+m.倫")YM2FЍO+kiPOtGAuA.V$["%`15j Y5Isu"!eԝ2i7PԵ Z=(R@J4䠂>xOmwPghFZ5tVAmn,‘h$Qa-b.{\Kd)j !<0+O-fMJ}&==J÷*=vZeC6aOuRX-C&CoKPү!OuI>,yбj{_|0|au$hܚmf@0C41=Air&.#fX•Q$͛6lٳf͛6lٳf͛6ljӮ͛6ld^qGO޴͛ە>f͛6Sޥ8Pҝ\ÂtOJ{S/6P)zx͛/~ʟk+1zwlٳf~[.5͛6lٳf͛6lٳf͛6lCm>w>: z_џ>J?YߣJ-˞-sO?*}/ˎէg1Y+Hz֓{dN{fֿIjz_[H_pʧ \蟨j迬JWtޜkS~Ҿ-oG>GߡJ~N_VSOGCS_ZkSőr?0K%ZG̍v1#3E(h$': {<÷^?/:iǏ }{{oSoON>ּOSV'埬kUy}~>\Wk_M^S8?G~y}cioO٥+ʻOk뺧G?QIGԯ*Zqߎ6U/Ե_zW'ozp{>BK>NQzޯ>?Slޏ XYkEYn7,>}o*jg_kÒO&};lCpٹynTpmJ= ;I/oTjQ8B}g> Jg&Nn9"C}g;Jzm'z_!~۝}^?~=Rq*~=S>OOܫˇx^t-+OW[>ԿIzZ~F z_SO~/OOmֻ?ֲVEet*H;uo5~_}@޷K)ΛSޘ.O O}xzR/sۧyvȟ_<t4_K1f&7Oq˗_zMѺJ~m|~A}o8l>U+sxzZ/VhU/~ϩ[w}zz_OCg?IW~߯_AW_Cڕ\!C:4O54["_E>eT)X9z|A`H}!E4֥7H W"XgR͟ endstream endobj 116 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 62.022 429.4487 Tm 0 0 0 rg 0 Tc 0 Tw [(extent)-256.9(of)]TJ /F7 1 Tf 3.8014 0 TD [(in)-255.8(vitro)]TJ /F3 1 Tf 3.1851 0 TD [(protein)-256.8(binding)-255.6(of)-255.6(ION-353382)-254.6(in)-255.8(WT/WT)]TJ -6.9865 -1.1116 TD [(and)-263.7(HO/HO)-268.3(plasma)-263.5(from)-264.7(triplicate)-268.5(samples)-264.4(was)-270.1(comparable)]TJ 0 -1.1174 TD [(and)-252.1(highly)-248.8(bound)-247.4(\(98.4)]TJ /F8 1 Tf 9.5093 0 TD ()Tj /F3 1 Tf .7142 0 TD [(0.01,)-252.1(98.4)]TJ /F8 1 Tf 4.1643 0 TD ()Tj /F3 1 Tf .72 0 TD [(0.21\))-249.7(at)-251.2(the)-246.5(150)]TJ /F9 1 Tf 6.4566 0 TD (m)Tj /F3 1 Tf .5529 0 TD (g/mL)Tj -22.1173 -1.1116 TD [(level,)-322.5(and)-321.2(\(98.3)]TJ /F8 1 Tf 6.5488 0 TD ()Tj /F3 1 Tf .72 0 TD [(0.09,)-321.2(98.5)]TJ /F8 1 Tf 4.2391 0 TD ()Tj /F3 1 Tf .72 0 TD [(0.14\))-318.8(at)-320.3(5)]TJ /F9 1 Tf 4.1182 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/mL)-323.7(for)-320(WT/WT)]TJ -16.899 -1.1116 TD [(and)-280.9(HO/HO,)-283.3(respectively)-288.7(\(Table)-280.9(3\).)]TJ 1.0137 -1.1174 TD [(Plasma)-211.5(protein)-210.7(binding)-209.6(proling)-210.5(by)-209.5(SEC)-212.7(using)-207(Alexa-488-)]TJ -1.0137 -1.1116 TD [(labeled)-535.6(ASO)-529(revealed)-531.9(similar)-534.4(and)-528.6(near)-536.6(identical)-532.3(protein)]TJ T* [(binding)-670.3(proles)-676.7(between)-674.6(WT/WT)-674.9(and)-672.6(HO/HO)-677.2(plasma)]TJ T* [(\(Fig.)-290(5\).)-293.6(Following)-287.5(incubation)-296(of)-290.2(uorescently)-293.1(labeled)-293.7(ASO)]TJ 0 -1.1174 TD [(in)-255.8(plasma,)-255.4(a)-255.7(clear)-256.8(left)-253.5(shift)-259(to)-250(a)-255.7(higher)-255.5(molecular)-256.8(weight)-256.6(was)]TJ 0 -1.1116 TD [(observed,)-457.8(as)-452.4(the)-453.8(protein)-458.4(bound)-449(complex.)-458.3(The)-454.9(addition)-453.9(of)]TJ T* (0.5)Tj /F9 1 Tf 1.4169 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(M)-652.8(o)0(f)-653(nonuorescently)-653.5(labeled)-656.5(ASO)-655.7(\(ION-353382\))]TJ -1.9698 -1.1174 TD [(slightly)-187.7(displaced)-186.3(the)-183.1(complex)-189.9(to)-180.9(different)-191(extents)-182.9(with)-189.8(a)-180.8(4%)]TJ 0 -1.1116 TD [(8%)-567.7(displa)-7.8(cement)-570.2(in)-572.5(WT/WT)-571.2(and)-568.9(HO/HO)-573.6(plasma.)-572.2(Free)]TJ T* [(noncomplexed)-219.7(ASO)-218(was)-212.5(determined)-223.3(to)-215.4(be)-210.7(between)-219.6(7.5%)-215.1(and)]TJ 0 -1.1174 TD [(15.7%)-279.6(by)-284.4(peak)-277.4(area.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 62.022 243.1558 Tm [(Total)-337.5(protein,)-333.7(albumin,)-332.9(Ig,)-334(and)-335.7(HRG)-331.1(evaluation)]TJ /F3 1 Tf 9.843 0 0 9.843 72 226.7149 Tm [(Total)-422.8(protein)-423.8(was)-425.6(determined)-424.9(by)-422.7(Bradford)-425.6(Assay)-427.6(while)]TJ -1.0137 -1.1116 TD [(albumin,)-376.7(immunoglobulins)-376.4(\(G,)-375.1(M,)-374.1(and)-373.1(A\),)-375.1(and)-373.1(HRG)-374.7(were)]TJ 0 -1.1174 TD [(assayed)-454.3(by)-451.5(murine-specic)-458.9(ELISA.)-455.5(Total)-451.6(protein)-452.6(concen-)]TJ 0 -1.1116 TD [(tration)-389.4(in)-382.5(plasma)-384.5(samples)-391.1(\()]TJ /F7 1 Tf 11.3524 0 TD (n)Tj /F8 1 Tf .6624 0 TD (=)Tj /F3 1 Tf .72 0 TD [(7)-387(per)-384.6(type\))-386.9(was)-385.3(similar)-384.6(and)]TJ -12.7347 -1.1116 TD [(comparable)-569.9(\(54.6)]TJ /F8 1 Tf 7.4991 0 TD ()Tj /F3 1 Tf .72 0 TD [(20.7)-559.7(and)-563.2(50.4)]TJ /F8 1 Tf 6.2378 0 TD ()Tj /F3 1 Tf .72 0 TD [(13.4)-168(mg/mL\))-563.3(between)]TJ -15.1768 -1.1174 TD [(WT/WT)-231.4(and)-223.3(HO/HO)-228(mice)-232.7(\(Table)-229.1(4\).)-224.5(Total)-227(albumin)-229.2(was)-224(also)]TJ 0 -1.1116 TD [(comparable)-287.7(\(46.5)]TJ /F8 1 Tf 7.2169 0 TD ()Tj /F3 1 Tf .72 0 TD [(7.5)-282.1(and)-280.9(39.8)]TJ /F8 1 Tf 5.178 0 TD ()Tj /F3 1 Tf .72 0 TD [(9.8)-166.9(mg/mL\))-281.1(between)-282.9(WT/)]TJ -13.8348 -1.1116 TD [(WT)-253.3(and)-252.1(HO/HO.)-254.5(Total)-250(IgG)-257.6(was)-252.8(determined)-252.1(to)-250(be)-256.8(107)]TJ /F8 1 Tf 21.8235 0 TD ()Tj /F3 1 Tf .72 0 TD (8.74)Tj -22.5435 -1.1174 TD [(and)-615(116)]TJ /F8 1 Tf 3.7265 0 TD ()Tj /F3 1 Tf .72 0 TD (11.00)Tj /F9 1 Tf 2.4133 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/mL,)-615.2(total)-611.8(IgM)-608.9(was)-615.7(21.48)]TJ /F8 1 Tf 12.3488 0 TD ()Tj /F3 1 Tf .72 0 TD [(9.49)-611.5(and)]TJ -20.4815 -1.1116 TD (21.74)Tj /F8 1 Tf 2.4191 0 TD ()Tj /F3 1 Tf .72 0 TD [(9.67,)-188.7(total)-191.4(IgA)-194.2(was)-195.2(12.64)]TJ /F8 1 Tf 10.0795 0 TD ()Tj /F3 1 Tf .7142 0 TD [(5.27)-196.8(and)-188.8(18.24)]TJ /F8 1 Tf 6.0016 0 TD ()Tj /F3 1 Tf .72 0 TD [(9.07,)-188.7(and)]TJ -20.6543 -1.1116 TD [(HRG)-351.7(was)-350.7(19.1)]TJ /F8 1 Tf 6.2723 0 TD ()Tj /F3 1 Tf .72 0 TD [(2.2)-351.2(and)-350(9.39)]TJ /F8 1 Tf 5.3162 0 TD ()Tj /F3 1 Tf .72 0 TD [(1.35,)-350(each)-353.5(for)-348.8(WT/WT)-352.4(and)]TJ -13.0285 -1.1174 TD [(HO/HO,)-283.3(respectively,)-286.4(at)-280(\()]TJ /F7 1 Tf 10.4135 0 TD (n)Tj /F8 1 Tf .6681 0 TD (=)Tj /F3 1 Tf .72 0 TD [(7\))-278.6(samples)-281.7(per)-286.7(type.)]TJ /F10 1 Tf 8.9663 0 0 8.9663 62.022 84.2456 Tm [(Plasma)-333.7(proteome)-332.9(ngerprinting)]TJ /F3 1 Tf 9.843 0 0 9.843 72 67.8047 Tm [(By)-302.7(two-dimensional)-309.2(gel)-304.1(electrophoresis,)-312.5(using)-299.2(isoelectric)]TJ -1.0137 -1.1116 TD [(focusing)-199.9(in)-198.2(the)-194.7(rst)-200(dimension)-196.7(followed)-201.1(by)-198(SDS-PAGE)-196.4(in)-198.2(the)]TJ 25.504 37.8528 TD [(second)-365.8(dimension,)-355.6(a)-359.4(clear)-360.4(separation)-365.9(of)-359.3(major)-359.3(plasma)-361.4(pro-)]TJ 0 -1.1116 TD [(teins)-283.2(was)-275.8(observed.)-279.3(Major)-278.4(banding)-279.7(patterns)-281.9(between)-277.1(sample)]TJ 0 -1.1174 TD [(types)-444.3(were)-445.3(observed)-442.9(\(Fig.)-445.5(6\).)-437.6(The)-443.4(presence)-445.2(of)-445.7(signicant)]TJ 0 -1.1116 TD [(isoforms)-263.1(near)-254.4(a)-261.4(molecular)-256.8(weight)-262.3(range)-255.5(of)-255.6(150)-170.3(kDa)-253(at)-262.7(a)-255.7(near)]TJ T* [(physio)-6.5(logical)-321.5(isoelectric)-328.1(pH)-325.6(was)-321.9(conrmed)-329(to)-324.9(be)-320.1(A2M)-321.9(iso-)]TJ 0 -1.1174 TD [(forms.)-211.5(Bands)-209.1(representing)-212.5(ID13)-207.9(were)-209.2(A2M)-206.7(related,)-210.7(and)-206.1(ID4)]TJ 0 -1.1116 TD [(was)-402.6(identied)-398.4(as)-400.6(transferrin)-400.3(precursor.)-401.3(More)-398.1(minor)-398.5(differ-)]TJ T* [(ences)-227.7(between)-225.3(expression)-226.2(levels)-227.9(of)-221(much)-225.7(smaller)-224.4(protein)-228(and)]TJ T* [(peptides)-287.7(can)-282.1(also)-282(be)-279.8(observed)-281.6(as)-285.4(outlined.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 313.0582 314.3621 Tm (Discussion)Tj /F3 1 Tf 9.843 0 0 9.843 323.0361 297.9212 Tm [(ASOs)-218.9(offer)-219.7(signicant)-215(advantages)-223(as)-216.3(a)-215.4(modern)-216.3(therapeutic)]TJ -1.0137 -1.1116 TD [(delivery)-287.8(platform)-287.9(and)-286.7(continue)-282.1(to)-284.6(mature)-286.7(for)-285.5(various)-285.3(targets)]TJ T* [(in)-324.9(numerous)-322(preclinical)-328.3(and)-321.2(clinical)-323.8(development)-322.4(programs)]TJ 0 -1.1174 TD [([27].)-313(To)-308.7(be)-308.6(effective,)-317.7(ASOs)-311.1(must)-305.1(be)-314.4(well)-306.2(absorb)-7.5(ed,)-306.3(distrib-)]TJ 0 -1.1116 TD [(uted,)-469.9(and)-465.2(ultimately)-470.2(transported)-469.5(into)-465.4(productive)-468.6(compart-)]TJ T* [(ments)-249.7(to)-250(reach)-245.1(the)-246.5(target)-251.1(site)-247.5(of)-249.8(action)-245.3(such)-247.3(as)-250.8(the)-246.5(cytoplasm)]TJ T* [(and)-269.4(nucleus.)-266.8(Yet)-264.7(ASO)-269.8(delivery)-264.8(is)-267.1(challenging)-269.4(in)-267.3(many)-266(ways)]TJ 0 -1.1174 TD [(as)-423.6(a)-417(signicant)-422.3(portion)-416.9(of)-416.9(ASO)-419.6(distributes)-422.3(to)-417(the)-419.3(nonpro-)]TJ 0 -1.1116 TD [(ductive)-194.6(compartments)-197.8(and)-194.5(is)-192.2(endocytosed)-194.1(into)-194.7(lysosomes)-196.2(and)]TJ T* [(endosomes,)-362.1(where)-354.3(it)-353.8(is)-353.5(hydrolyzed)-359(and)-355.8(metabolized)-358.2(before)]TJ 0 -1.1174 TD [(reach)-9(ing)-279.9(the)-281.1(intended)-282.1(target.)]TJ 1.0137 -1.1116 TD [(Clearly)-443.3(dened)-440.8(mechanisms)-442.9(for)-441(ASO)-436.9(uptake)-441(have)-444.5(per-)]TJ -1.0137 -1.1116 TD [(sisted)-376.3(as)-371.8(a)-370.9(major)-370.9(challenge,)-369.6(and)]TJ /F7 1 Tf 13.6793 0 TD [(in)-370.9(vitro)]TJ /F3 1 Tf 3.4155 0 TD [(systems)-372.5(are)-374.2(often)]TJ -17.0948 -1.1174 TD [(limit)-7.3(ed)-251(in)-250(their)-254.6(ability)-257.1(to)-250(predict)]TJ /F7 1 Tf 13.1379 0 TD [(in)-255.8(vivo)]TJ /F3 1 Tf 2.9662 0 TD [(outcomes)-254.2(often)-254.4(with)]TJ -16.1041 -1.1116 TD [(poor)-534.3(correlation)-528.5([2833].)-529.5(Seemingly)-531.9(major)-532.1(discrepancies)]TJ T* [(exist)-461.8(with)-460.5(unclear)-460.6(outcomes,)-459.2(yet)-453.8(we)-459.3(suspect)-459(and)-459.5(conrm)]TJ 0 -1.1174 TD [(hepat)-8(ocyte)-295.9(surface)-293.2(proteins)-298(such)-299.1(as)-291.2(A2M)-298.8(could)-294.8(be)-291.4(involved)]TJ 0 -1.1116 TD [(in)-365.2(major)-359.3(shuttling)-361.6(events)-366(related)-362.8(to)-359.4(productive)-364.9(and/or)-365(non-)]TJ T* [(productive)-255.5(uptake)-251([34].)-249.7(A)-249.6(signicant)-249.5(amount)-251(of)-249.8(studies)-250.7(have)]TJ T* [(comprehens)-9.8(ively)-421.6(described)-422.2(the)-419.3(PKs)-424.3(and)-419.2(biodistribution)-420.3(of)]TJ 0 -1.1174 TD [(ASOs,)-487.3(yet)-476.9(insight)-486(into)-477(mechanisti)-10.2(c)-480.3(differences)-483.1(related)-483.7(to)]TJ 0 -1.1116 TD [(major)-284.5(serum)-278.4(protein)-279.8(knockout)-280.8(models)-279.6(is)-278.6(lacking.)-278.7(Therefore,)]TJ T* [(we)-246.1(sought)-242.7(to)-244.2(evaluate)-249.9(the)-240.7(hypothesis)-248.2(that)-242(knocking)-246.3(out)-245.3(A2M)]TJ ET q 1 i 191.622 732.019 m 552.189 732.019 l 552.189 559.559 l 191.622 559.559 l W n q 360.926 0 0 172.46 191.622 559.559 cm /Im3 Do Q Q BT /F5 1 Tf 9.845 0 0 9.845 62.022 687.1746 Tm [(FIG.)-342.5(3.)]TJ /F3 1 Tf 4.1231 0 TD [(In)15.3(hi)15.1(bi)15.1(to)15.1(ry)-324.5(ef)14.1(fe)14.1(ct)-331.6(li)20.7(-)]TJ -4.1231 -1.0135 TD .024 Tc [(ver)-570.1(e)-1.2(xpos)-5.6(ure)-565.5(r)-5.8(e)-1.2(spo)-5.8(n)0(se)-565.5(PD)]TJ 0 -1.0077 TD -.0275 Tc [(mo)-5.5(de)-6.6(l)-356.9(f).3(o)-5.5(r)-356.7(IO)-6.3(N-)-5.5(353)-5.5(38)-5.5(2)-356.7(t).1(a)-6.6(r).3(g)-5.5(e)-.9(t-)]TJ 0 -1.0135 TD -.0273 Tc [(i)-5.4(n).5(g)-310.5(S)-5.1(RB)-6.3(1.)-312.8(L)-6.4(i).3(ve)-6.4(r)-310.5(c)-6.4(on)-5.3(cen)-5.3(tr)-5.3(at)-5.4(ion)]TJ T* .358 Tc [(i)379.9(s).1(p)380(l)385.6(o)380(t)385.6(t)385.6(e)378.9(do)380(nt)379.9(h)385.8(e)]TJ /F7 1 Tf 6.8815 0 TD 0 Tc (x)Tj /F3 1 Tf .4204 0 TD -.0233 Tc [(-axi)4.3(s,)-383.7(whi)4.3(l)4.3(e)]TJ -7.3018 -1.0135 TD -.0274 Tc [(p)-5.4(e)-.8(rc)-6.5(en)-5.4(t)-305(i)-5.5(nhi)-5.5(bi)-5.5(ti)-5.5(on)-310.6(com)-6.5(p).4(a)-6.5(r).4(ed)-310.6(to)]TJ 0 -1.0077 TD [(s)-5.3(a)-.9(li)-5.6(ne)-334.9(co)-5.5(nt)-5.6(ro)-5.5(l)-328.1(i)-5.6(s)-327.8(p)-5.5(lo)-5.5(tt)-5.6(ed)-333.7(on)-333.7(th)-5.5(e)]TJ /F7 1 Tf 0 -1.0135 TD 0 Tc (y)Tj /F3 1 Tf .4204 0 TD -.0239 Tc [(-axi)3.7(s)-364.5(t)3.7(o)-364.6(o)3.9(bt)3.7(ai)3.7(n)-364.6(s)4.1(imu)3.9(l)-2(ated)-364.6(an)3.9(d)]TJ -.4204 -1.0135 TD -.0271 Tc [(p)-5.1(r).7(ed)-5.1(ic)-6.2(ted)-310.3(E)-.5(C)]TJ 7.3837 0 0 6.5625 111.685 605.8203 Tm -.0316 Tc (50)Tj 9.845 0 0 9.845 121.6062 607.4644 Tm -.0277 Tc [(va)-6.8(lue)-6.8(s)-304.9(f)-5.7(o).1(r)-305.1(b)-5.7(oth)]TJ -6.0522 -1.0135 TD -.0268 Tc [(WT)-5.9(/WT)-334.2(a)-5.9(nd)-338.8(HO/)-4.9(HO)-5.6(.)]TJ ET 62.022 523.842 490.167 .28345 re f 62.022 476.447 490.167 .22675 re f 62.022 505.19 490.167 .22681 re f BT /F6 1 Tf 9.845 0 0 9.845 86.2866 539.4896 Tm 0 Tc (Table)Tj /F3 1 Tf 3.0002 0 TD (2.)Tj /F6 1 Tf 1.2496 0 TD [(Pharmacodynamic)-334.8(Model)-333.7(Parameters)-332.7(After)-335.2(a)-334.8(Single)-335.2(Subcutaneous)-332.6(Dose)-338.4(of)]TJ /F3 1 Tf 35.2768 0 TD [(\(0,)-333.6(5,)-332.6(15,)-333.6(30,)]TJ /F6 1 Tf -33.3305 -1.0135 TD (and)Tj /F3 1 Tf 2.05 0 TD (60)Tj /F6 1 Tf 1.169 0 TD (mg/kg)Tj /F3 1 Tf 2.6029 0 TD (\))Tj /F6 1 Tf .668 0 TD (of)Tj /F3 1 Tf 1.3302 0 TD (ION-353382)Tj /F6 1 Tf 5.4418 0 TD [(in)-331.6(Both)-334.2(Wild-Type)-335.7(and)-337.8(Homozygous)-334.1(Mice)]TJ /F7 1 Tf -21.9228 -1.837 TD [(Dose)-334(group)-5826.7(Observations)-337.3(\()]TJ /F3 1 Tf 16.5904 0 TD (N)Tj /F7 1 Tf .7198 0 TD (\))Tj /F3 1 Tf 6.1559 0 TD (E)Tj /F7 1 Tf 7.3837 0 0 6.5625 299.1117 509.7825 Tm (0)Tj 9.845 0 0 9.845 306.085 511.4266 Tm [(\(%\))-5820.1(Gamma)-335.6(\()]TJ /F9 1 Tf 11.1428 0 TD (g)Tj /F7 1 Tf .501 0 TD 5.8229 Tc [(\)E)5822.9(C)]TJ 7.3837 0 0 6.5625 493.9085 509.7825 Tm 0 Tc (50)Tj 9.845 0 0 9.845 504.6235 511.4266 Tm (\()Tj /F9 1 Tf .334 0 TD (m)Tj /F7 1 Tf .5471 0 TD (g/g\))Tj /F8 1 Tf 1.9522 0 TD ()Tj /F7 1 Tf .8811 0 TD (SE)Tj /F3 1 Tf -48.6712 -1.9003 TD [(WT/WT)-10215.9(20)-9135(102.1)-7562.5(1.33)-8511.7(5.49)]TJ /F8 1 Tf 45.7459 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.95)Tj -46.4657 -1.0135 TD [(HO/HO)-10465.9(20)-9636(99.8)-7561.5(1.34)-8511.7(2.85)]TJ /F8 1 Tf 45.7459 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.33)Tj 7.3837 0 0 6.5625 536.655 487.1054 Tm (a)Tj 6.5633 0 0 5.8334 70.0157 468.5101 Tm (a)Tj 8.7511 0 0 8.7511 72.9637 464.5983 Tm [(Statistically)-334.1(signicant,)]TJ /F7 1 Tf 9.8342 0 TD (P)Tj /F8 1 Tf .7839 0 TD (<)Tj /F3 1 Tf .7126 0 TD (0.05.)Tj /F9 1 Tf -11.6675 -1.0236 TD (g)Tj /F3 1 Tf .4988 0 TD [(,)-333.1(hill)-334.9(coefcient;)-329.8(E)]TJ 6.5633 0 0 5.8334 141.959 454.2235 Tm (0)Tj 8.7511 0 0 8.7511 145.2472 455.6408 Tm [(,)-333.1(lowest%saline)-336.1(inhibition;)-329.4(EC)]TJ 6.5633 0 0 5.8334 254.6645 454.2235 Tm (50)Tj 8.7511 0 0 8.7511 261.2409 455.6408 Tm [(,)-333.1(concentration)-334.2(required)-332.2(for)-330.5(50%)-337.3(saline)-334.6(inhibition.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (230)Tj 46.1699 0 TD [(SHEMESH)-334(ET)-338.7(AL.)]TJ ET endstream endobj 118 0 obj <>stream AdobedC       h s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjz?NlNT)$`*h*NZ}:ukkpi$pƃ_"cdMRUHf_ ^D`ٳf͛6lMyO-RKb#pl LVxf*ojj`y#@󞳫N+{WW1k֫sR<s'SAlouR"eh;1 [TԱӞ7uKm5(t(iQ%V:3 elP˺yeD6pW8}dOn٭0]kW1e>L9U(7/yY󥿓?EjVɂ!DX8<ĭm_gϠ~b7iaJ, cT=EJy)M\36^vךu쩥.<<$Ds#WG5OJ4 Rkke$I}F.So7ZږhhТ}]ns$.ڤNDWF+) #/6lٳf͛6lٳf͛6lٳf͛ U?ߥ3KolarV3n䱔 ?DEZ7_˷婞 fGs$YjTWN?-bk4iW6FQ[Hn{ᯙ|8/6lٳf͛6lٳf͛6lٳ~x|CO a&R?kۿ̸M MҮt nRiU"ut"3BOum^z//nRKÏLfSd6lٳf%8\kmy6HN-Q "_SS9-&VeEIRQ__'uD4:M&lSkQEMsM@mJ%mZi$oXJ]yh#8^ (~m[{X75hH*9YZ޻S%Cs2ʾi涓&ҮcԂ rfC$g29{] iknxV9Ϯ7'ԇs%ŚJpΪ93|8<Ǥ^z3B_KorE^?M3L_^aֿ'߮]:iFܘ`cQf͛1 YA{ [襻S_w70Zsp8!RHƁT r'gڶ!>\ʞn׭S\-Ȭrޕ\}XE5Z1qc'07Z 'O7O7\ok7QGq'a~nGڕǒ+t1~pŬG3$znJQ_Z῝?8<ڿ=5y\2=ԯio]N= `߼3nd6Z[dKȾnռ8`;!H9 ~L5S.iPȡUgk~9wb~T ~Z{BX@eBwZ.£|~v|xn5]].i} o(܊Q͛6lٰ3hj+}_5N?dߚZ6d y5 )-;wZ~0r=_Y9|*i羲uI"+? Nf8OTʧ|OJKOgPq8ikNTWRӚnhP)U>Z *ϚbnxDzeVTq"+mX{}b;XnSUIY/1C.i!7:U 3M]}Rļ#_QWUP=N'uK~?6lٳf[-K?̯2ё8ΚvŬ}NmdϟabՖjj0O( 4lw/O7;zy4UWjLkM/Ź.T-Qo.zɄQ=[{#YiiVEyDMε,ꊝ:|>y7M-$OY@-I_΃/ 䙔fm1Z!nT^d ;dFC訊T|o_y|rkiwgNKUxS( IM)>jzw.ᴅ$RkpE'*8Q:_9nm}2d}L3f͛kiWIM(ULr].5N_QM[f>6N"]ә|gw5Ņ"$ż0~_˫mRjΤ/6[0Ȥp{sGk?'K~a7 ޳ʶȤБLߔ0/t. 'qLsf͛6lٳf͛8N?̏Ο;vlٳf͜c;Fg| \)6WK6; /埞2j}C̒K$ I$Eܚ-@]P׭"_| ui*IVr `ev; y_;yoJWtRj x;0=BXT'm¯^XqEq%7,~*a}h%"$Q W:Flٳfio՜gqwQ1^Yf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l&q~dty۳f͛6l uiWvvLkqJI1F ‡|6lٳfqn1C"̑H9'-*:f͛6lٳf͛6lٳf.q9>Wm?@";N)nnoQ-Ƒ!lX.7Iom7̚`Kd{$SAV'h讦}^l؝/.;/kvٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6#y%vk5ʩ0YfނrSͯ2yYtt(ɊG"|p~U|v |yʗzn2~AA 9:P6lٳgn͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6q3~guO1k_Y@H)݉1k #=~T^KW̐naL,OՖ_DGTӳf͉߫8bjO2C cra1\OjJIl?֏܉+471Ho6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l:֑yߩ{;^Tn)Sņ5_ 麜Z//f&,g9*Y唃$N4VMƝ$yϧ)U^9Pv8͛6l&q~dty۳f͛6lٳf͛6lٳf͛6lٳf͛6lٳf͐+-sSi6=:mȰ "IQ$*E-%{㼣[5`{ky.#|WPȞ?M4[nt{)f7U'f͛6r/O1/6y"]2)Iܽ]3.. qZ҆I*˯aɥ~ utn$RH:|lٳdS O*igku>|I[͟(\i3jʑ@k.~8RwsGr z/'a:Vu MDŸe^xgʃt3w~kyu|e]kv[eX(.ej*iU:jH^X$rWeF)g^O/$2M;2zme`P2Ǯ\Ϯhn5K3l^+}j EKU? )O:](xN"Q{ ^S"^<zg`͛6rΘ|6ۋ>˳SeT =)?v[-im-G%{5(ޕcYyi Hd]+ +˫M/ϓ^L#Dnd4+OQ+,N"RچC٘on#I˂2͛6lٳf͛6lٳf͛6մ[NNմ^FJCE?M~]ձ&eʚcMT3uV~q>F[_[F@@.jzw>g䫍+C]=vG~F6VoBf~\jƿcCc6Si]ːH;qi|Z-ZfD,>_a7+em=َ_KD~\nFɹ򭆗.m΁=|oPڵWz7~\k.G<=6~x:Oaq%Y_g^*UP(͛6lٳf͛6lٳf͛6lR"Ȍ* ;ɯ˲I:cTnoS_loIM~]ձ&dKhKҡ-T?vz?n _.I%csEpNeyWx%b: /'垯}?,I*΅xSkYy+ZEh\'g>]J\(^Z~_hHkqmrڥ)0$2Z+0'g_=zߔMK7Zk?YUbTx8x\!/i>ncB8`o)AHtмVRXh[G'pJ~\躮;[U;y8ۚVz~~mkUǗVUy"ic tm~\j^do[_:"96AK)f̀u2R.-oKwF&7qOH:kTyN=3z[Ojd3I1_Ւ^\1}uiku$#q˷ab~ 1Lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͜_JDHu#z{KM\zvɥN>%彦-֣3[k~i=LN4ks͛6l55ذ!)[fF{UWЬ58I1AO_A ٳf͛6lٳf͛6lٳf͛6lٳf͛6lٲeNaӼA{GEo,% ө=07?uyiQ-5. QP3͛yQVqG|m{rk^KIZ~^vkY"Bi6Zkz-hܭ"YSڣp~Gl6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳg-me6\_A%rLYfQ@0|<-uA4N\,/$@eE7Of͛6lٳf͛6lٳf͛6lٳf͛6lٳfY?0t['Hf]+VъLnI1qd0x u!^cz͂6Z;LVDy2V6oI#5 6l؝/.;/kv~gh4Z4)Zyۑ"Ta5O0h6ZaV}Lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳfasavnxgJҩ"aQc?>JoG_5 "Ԩv+@ZwUu#%=k:ϯIc(qIR Of͛6qɿ_?^L4ٴۏ.y\FV\ⲲSUaP}>r#JŖ(!_$(p:cs[ŦNIn sE24"iAPw6lٳf͛6lٳf͛6lٳf͛6lٳf͐?3l]GK'{)"ѓ=~.<c,T~_?,/4SAyj a$ea-ǏmSgKi6ַ7TyXvEb i5-V="Kt%^qX&eay;_g\w_ןYP9|_(y/hk\uM~gF͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lAe=7HnD<)>_֡Iм't˳sM+U@1SZ+'LIЭ4ǽkuJ:Zj+$폔uk i 4E`6$75{[_3Ki{Kog -DJ/F]RR4eLs;n#Olk>m,qk,iu4qZҠ9Y3՜:cxf6x:0Uaαהu]4SŻhrSO\7+QfVHnYPqu٢Ϫ騖yk4wVɒ?2Ǥ\[3_]"8eFA ?;4 Gm6lٳf͛6lٳf͛6lٳf͛6lٳgߓl]S"1IrY>?uk,ch(!]ԗ#d5~aXih[u5N}_He{{ADiI8+4_NrX ƆRt j@e;F@-?^+E[ wi} Riٳf͛6lٳf͛6lٳf͛6lٳf͛6lW_W{&\z?Z/aռj]7H8^Ex×ʜjxu6lٳMfak)eèZ[^ib"c$zdz}rDtoUn-ɊI8`6'j͛6lٳf͛6lٳf͛6lٳf͛6lٳiQsǤ_Z3ٌgbm:2\j:V"FgOLd]2Kna'. ִ^MKMi 1Iwg% 1 jE͛6l~Y,ͬ[4)Hw&!tMYiVHc5B=1Nw7֞[4ՙ$΄*qhbE$c^dcմey-$$%e}93f͛6A?1O/k^XO1~t 2zu(<7.|uƗ$<6BhUeäऋʄwQ9yέ{埪YyrKKMB9.$$UV,YZ <ҐkPi/3SCG"NŸf߮͛6lٳf͛6lٳf͛6lߝˤqMNS֠㗗4Ud Lnhgߕ:_p?5,J%՚C&y~ w;Z͛6'uK~?6lٳa/u4,<1W2-?&o`7es*oaYBz,癨^:}9!)I`H 1f͜3~~eh=u TQkIg5V$FȃOL{{ yzIiՄS׆B\<|Kz.;ε<6m[NE[j9 l8Ưħ مEh}ٳf͛6lٳf͛6lٳf͛6r5Ys?NL[yxΫdڍ#N:8Wqu3Wi,_ַ_X]vknHڻ`ٳf͛6lٳf͛6lٳf͑_?$`m5I&G!o[Х6Jl/I-u-{똭-cycG1g"oOeu&zUOyg(/bW׶ʠ 0F81;MhgK &&i-z}vq9WX g*˿д=FEPӭ$Q^xc aOϧ鶶s2i`85dPi3TϖiTҬR)n`fQ֊άF`i`A//-[ջ]>Y` @+Vvڇlb4ӭ<.o=7Y * ޹|{s}QWWVM <-+[M%{" !b2)y[+E6fgA$vr_fU(3Wޝ2[6lNFYo8Y4-OWƫrM62e=yg/izeVF꺄B kFӸ;w0_ SӨko~Yl˚m'u q ' uGO-k:DWݍWb˸u 1y{OF{ky%G /*봇þrm7JzFlcu n3TP\"3Xro9$n#BZR(J0?Dr 9jW yIkd QTr|i?(%CpsClٳam4[-FQ {r$vʆ%S. W5;{XỸL+`qyijp6lٳf͛6lٳf͛6lٰ>5uP Ȣw-I"*yL[y)ǐMaUא}_b;ɺƠ|ϤE Oh`S̑N;S$yf͛8?jkZDu6pYa2~rZt} mX\b҉o-8O/ڧ\%Go-&O".SyD`|sy#f$ióq)iG:ua] fdQptdrǥr#߮kߖGGtcZ-_"\ߐ<Ͽ7m6V24q,Q`YҧHy3qs~^5&!S^-"( ͛6j]ѵy-mjXVu8`C+FmS˚!w0 jrCJUTalٳf͛6lٳf͛6lٳ`{xQ鬓fOѼ-O%O?OB6A6lNFYg;Vl\.#S|ٳf^͕VDBj0`|g5_xɞ`6=2rs`'eAU2T7ٳf͐iou;kۉY!&dzRk;Z|wmfOmٍ~4ɖ%uuoio%Èwn i]^Mk];I9"I+ǵx킼0꺫aӭJҫ۹d6q?^vٳfi.c϶y.jvKy(ߦ6z5 !MAV9f͛6lٳf͛6lٳf͛6lٳf͜?'0KfļYCejRoZ$Ysa0u |j嘵; KܒFdb)¹`7?bYVi[JN^0ybME{m͛6lٳf͜Hɚs_iZ}b}aa쮯K^k[k IhӫȽV+$kS}gd=^2 [tyYUot]?h{f͛ꖲV?$Aц"V5 r4S/4ۥO!o,M͛6lٳf͛6lٳf̀.VﴻV -+*j}9NG8ծuojSiDž[O+DEGcNrEGed|iX_SI,t w,X.Hb9VpUF&usqkjP&Sy̰[ZRi Y!ǶH?/f|t m/LNBЗ}ɟ|ӘMȜ}(b5:/֧}yK_[[dW@"IR` AD:%uikwAuOӔrhj*z}ꐯLʟ NFYg;Vlٳf͛6l~SzkZj뺍+*/-z&-Ogӵ}ukC·kr?o4yBT巯)ИMMPv}iw6Ra>M#X9VHbKwhdH:6 (ʇ<ؼ.Vcf͛6lٳf͛6lٳfO<4uVys{;7U#AZP]2msDCo&-E+Y9UFnF_My^X,;M&HV5a_Jb6=&f͛8N?̏Ο;vlٳd[ȾX4)|׍WW-2M"(P~iΙM}+PJ(r)tfS! Xij:IBbXuVS#͛6lٳf͛6lٳf͛6lٳg9^\yPi<%1 E,߾}е*z`"SK1MhMǫj]=DvP2þǮNf͉߫8bj͛6lٳdA?3kב7YXJ`iC#K(@er4A5M6AɎһЃgĶվFNϟ?_SӗH3fM3̋$N8n)9v\9>-^mG2z|8;],n<刺&V;)H&9r}O,N*2F?6lٳf͛6lٳf͛6lٳaou4/jZALqTJ|5s8yv2h^J.n05Ou-4(3\nGKq4:u=CMxKxE9澤!RD&P6lٳf#7#3ݛ6l]b1_Ȳ&cdB4FU4Fw8q?2Z(,hyqK?h5Yc>-¬vS~Q kH, r1.c qҵ;k9K{Fe'CnkԮq8Jny*͛6lٳf͛6lٳf͛6lٳftyLu˝G˺E!z$9̱WaωE֯5ۛkDvj Ssf͉߫8bj͛6lٳdN]E^6_Mmu SL1փq}nUT$nAD*@^S򭷖Qv(*-ɐq콰6lٰ6ڝj[H(ʡƃ3]yY}9I=fj&Z:rּKO=hh5Aٍ?iZ֝wݼ,.Ӷ ͛6lٳf͛6lٳf͛62hadYaJI…X##>X?//VP@8l#GU@֕Gtx6sut-ü̡K3f͛6qɿ?^vٳf-G>tOC{VU=Mj0=^6mm=6I;'"lӼ>H—ofL|q56ZF~~o|y4Ĉ. MEcMwzTm'Q^!u6ɚH//6lNE' 'i^cuftoxubl--߄JZ)!<ȆLf͛6qɿ?^vٳfo懪wmqwfĩ t+$ҥO]=wkE^15[-.SQ .P׺&l_j:5i&fE樈Hz_Eծ]{xׂ 5(>Hf͛6lٱ >x]p Q_cC[WG=D1O7/K59tqM<YMW-*^Wd66ޟ)tyg`;,O0kɬ_h3ym(ZERJ9KTb{K\Ubdg#ZC)~Yf͛6lٳ3*@Q'kO垅-AYĉ }$N~'SL7't?+/Wd+0FQT{d6lٲ?]3wG5. :m"FO(Y\#3f͛ 4-Z=֭q`׍{zÁ3* Emf͛zNZ=mݴU 7ߖz|t[diaf]hЧfS_>fF$_-X5-CzF*Va\UK?.i,~zy=}f͛6F.0X.[12Xuzd #ĐʡuzS6lٳf͛6BO$GҴo9\Y+_.RNEc^ T /L.Ek;RN^d̶DL\nS{gE͛6'uK~?6lٳf͛6C+SWӵuq%i0Qd4@FLdgTu}Zm[Bݪ> m<[^\jڴq*!8^ܜ>͛6lٳf͐-OZ/ӼyeM:J=SG4.T w;vEʨ/Żmu-M[ƷaEknm-.xCȟ+ƓoՉZ7$EjdGDgy켷^SH6z:[v\<˟eQi~fJ#E.N:tsK]J"5ɯ(JYZ۔Y}/_s~\]]SQoOT X:XGulbhX:x21|ٳ`M_Iӵ2Kԡ7P1 _V qrS7LZbh/u$`h`X#Jn '>'%Y-XE՞n"@X8G^jŇ-"D-<ַKs=E$݁fw4lA2\ֳz~[k(+(*͛ |i^ywSӟ.-fZӄ΄F%rP -F[:s} j4Hz*[^kLsf͛6qɿ?ם6lٰ^ko5h/O$dE~kNf͛6lٳd_]P}u4ٌ@2DŸ!Z|Ni:YIy$fȬ`x ͚E/yn @%TG?GM"LuJYt.d>g֫~Z"OO|hZ_N3b{j2k\0X/!HOhgȥq,eR㪂*>vlٳf͛6lٳf͉߫8bj͛6lٳf͑/.j^k`@ѓN-͛6lٳf͛6lٳf͛5R6lٳf͛6lٳf͛8N/̏Ο;vlٳdStFq_ EB+\f͛6lٳf͛0tS/<˪Y3J:YHF22փydϧyQ=ͅ\4]Y\iƢh4剮-to-r- ߏF<_m:I?Q*jڛ7_{\-8;S#s~^jyi/5[HJn81DTg{Wi!l WrZ4_/ڬzuVgՠ,2a7淚좷k"-ꢹDwM>G;TT5m<7Q5AJ~u~[jYu[a?m2Z{^VA¡j%9f͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛8N/̏Ο;vlٳdSou;wu%VzɆ$b(Miٳf͛6lٳf-opj7B};P#{f]\~;` z;ndjWDm5@}ܷs{^\晚AHt"E"_>ȥ^V`cCP~!7SS u/{P4jhN#a#}9:O05җƳl<*Ypm0,c)P~lh :_)\רAfnͮ"[ܺ *b/.;/kvٳf͛6lSA#ъo''+VZ&۳f͛6lٳf͛6lٳf͛6lٳf͛6lٳ`w[4;V*NTwbv[;iikH.l`w3aU=F$9Mf͛6hzpƙtmuf͛6lٳf͛6lٳf͛6lٳf͛6lٳgc>sG ]CO FXk'6΁~}#1jv@oGnX6"<,̟&rR-qOq_[Zͮ(;i5KVoZfHr o+ricCԃ?7o"+[[#C 42EC!I!AFV?7Hs/oX #OZ?箱`wHA)Q9^̤`X E#O_+뿟\ȫ"\j2%IrܝG|#/Ԭt ^j>M_^rw/oX E#O+ricCԃ?iߞښܵYIiqIO4$^cCԃ?7ob9R _4\~ozYCwhbQZ)rg PX E#O+ricCԃ?7oob-#Wk?K, S9Eٔ+ricCԃ?7o"+[;#C֤fSWhe!AFV?7Hs/oX E#OΛy7]k`yte2C6lٳf͐ݼ(Asm,cI`0/_:U&K6_$wQѻ,@,64|s<-VOTYTS C~rˤ6_(E /?80EyۍJc$yB֝rOEfoMV/3'?jمf,|e"\]Y*{DtMV/0k9YyOmN^r q0Grs?5XȿŸ/Ik{$}6/(90yaGrs?5XȿEfkv:Mi?BV='JFp#99SU?_fNa"7GroQHgGţٜFr]RA?_e'?jٛ#99SU*䖊t?q0bvaGrs?5XȿEfoMV+06>`QWle11t%vMV/2?5XȿNa" 5KO;ZѴ|dkO韖z楮 Dյ6V.ܲ )pI6lٰ_Хգ$UxE|ѩW=9d8zuOl̈́b̚A'.xoٳdW%6NsfcR_4_LZF({qp6l??$lA,ɭ_h)8hڂߺO)#)6l~M'um}SelCyjMO>]VqLIOB=ʸ}6c!-tEK|ٳf͛6ldAq QԺj$7-NQN +pAkSf͛6lA,k fYK˻]NCf͛6lC_-+YLZIy{egmAu=E`ıR<m Ef)ѻS͛6lٲŬjGotlhՒ8@$eJ5h؇F\E櫯2`7 [i!4<o2y6lٳdXnytX\y}qcpū?g|$k0jPyn/Bw'':F~ez<(=ʊٳf͐?;k>n-'Bܠ nƧ!z&M杨yT撐[gl%=IZ7Ug!pZNiWmlٳf_su;o44$-!Hp<)uMVNL͵ƞN*Nuٳf̈́^x` U 6Ú0eؑ~Bu{7qoX8ANsf͛6lyo9,͛6lٳyDƹu.M}'MiVfYWykfփz:凉ӉSé9cEDT_yf͛9λdMVZsQ=9gf)59Ux!y{;ZZ^ oFkeCPs"Pї6lMˉ*AIQy}gVtE^c^6d| ׶6q,jWw)EOҌΦE/6lٳf͛6li˩i7{7u Ú\yp\ 6%~)N@$&:Nlٳf̈́ko4&dV:otޜNpa`TPܐaІͭ\؟DL[5垰ܚr#$XT p'15{Cgu-62[Fc9D҇4|Ǩ4.&Ѭ7"A r^}`)ȕdx;~tuZXYhCA<\}f,*ZM_@ǫsFMFMa'• oOGח <uV~Z,4WMͬfdXZ:ȶ|Wa(cPfi$'s=yX'Zu]~ȿX Uxr5*i{Kt8Zw8UkxK/y_FO׆YFZStϔ>Qf vZ΅}f- e[W 8G=F֚ϓ|O=yjˣkn=[VSy-?;32'~B/1Z=5M*GR +|?/>[+-3^G+UHKB2 G\hڏ)g4ŷhu0Cb$fG%0|#:bi7èy]R3z"EC0%#6ۃ *4+jZ?tQOƺ̲j^WU;R$lѴ2(XSy>@bh6N$P>.]A޸Ie6_,1:\+unT25[J j~\󧔇죰ˇյ_O1:HrVM~oyzƯ`B obT,RщkC^UY`y̽>7'Ƹ_-y]oΖQ$= n2K-7ז2:H֍B6,'^/Al{]u-ėx"jzho]NeoP}ךX[-?$I2#/ʤBUߓe<+I]JK>cw}Ff͛6lٳf͛6lٲ R~Py<6/,,FJ2xyFʺLV$Q8QSv9,.7Ghk|7%>x$X'uJ;}2S84!vg-=}BoT Xv|]m5+אY}-q2I<}@gL~ZdzTv[Xb< H8w9[y[!MBTQ,vVQU g`*KҖ`A3U |ۙXeU/K˰Q"[j7mdbXݣUaԺnl|ɥf$a7խYddYh>g=`FOVJ {9yM˾[RXԂԁw-q(VN×jW~`/]^Cmpc+GazmG;އ鿑zmEkYUGb\|;u/0pk_@y?M/Pr8'!E܍͵äbXϜttr%͐ ٍJzGnmʾiS#gSsXgyI]$ˤ~U[ZFKxh92XԟM'mya\/QE؏\Nd xS/K:׵-[]3A XXxs۩?ɗI{v h+[IY=>;3:TF/zƍ0yO"kd d{bU3z!#]7C_E-ƕ~^)o+V?'2#2ƊQkÿ˫=Κw.KR;*Z ,0Ar{Tح75l2򥎇3.FlaأmM I!8ѫۗ83Ϻijy>LAMsuhZO02j;u|hpe^@Mo$w]{Kr[Su!⢊ -u.yŲ4KthN&Ypi%lPy.G;DMN$hRHՌArdff;/z |kʫ/+;#X5 2 KeE YB$ـ=C2M sFj(t>*1f͛6lٳf$1P{TygZ/'PM4`ML)$47?ASi>B:>jGY-?Qe*a8E~Vj&xt3Z^MA`\Jw5/'ȴ~^y>(yq4I/O<3NT<4ZCYRqak^t(ፄ.bdfLjZjX{>P?WzzvÇkJ͖moEim%^68ҕ2Σ _E:Ey[X]QxqzF o=y"B$kvRRxrܾz?䵥켷u<7ͪh0M3΅G +C7Μ|ϨG}aΗi)a)n I30C@5an/J$/3#c뀼y6Z:5b.貥#r]"Fa/j[KeΤi6ZdOjbiRJޢH= `3[Mt]3zh~m[ V䭹;_XcvwvհS/5WM)1yGT5TzwW,lbUcґ>:')<׮>؍.hS`?NR2զv,X~@`KsϩQ޷=RH>%"FH;P&>Y^|6\-ơipW3vE8 aR_7y+U!i'"!i]c̞cE,y71AqE,2ȥdYb0F[RͶ}nI+[X G<(oT%9TP@wm62j6W-I[Ok{c/1q(=;8-i+,fv_mmᵌIsV%;q!je{%yEKٽc7TQ{RSɖ=ċ-kyBIf͛6lٳf͛6lr+6"6ʍ DnQY*N矾izńze[oqqGu; EQW.Ko1Z5+JH㍑T^$3P+4o-2ח]G,zvb6ʵƫjߒＷyv db#$3\)f>QB*N:-KpP L`,CT琍3Z5RZz>rZ=2:Au%=YmѕdZ6W3^BiڙMwNVӵ/NEwTA^Ukhg ﯭ514T8ݠWi_$۫~X]a};^7$w%LT?hw _+y6z{sc}+p@G7yοiZVzVokjAYj,[y PU=6?0-t_//λgc5Nwe'pHC'+FyO5f{*˺U1istVAY&2Hf\ըK{k?3qӣ5ILW+r yRVDfa^pY>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 59.7543 407.3385 Tm 0 0 0 rg 0 Tc 0 Tw [(may)-316.7(alter)-319.1(the)-315.6(ASO)-315.9(transport)-316.3(process)-320.6(effecting)-318.9(the)-315.6(suborgan)]TJ 0 -1.1116 TD [(distribution)-284.3(leading)-281(to)-284.6(variable)-283.2(pharmacology.)]TJ 1.0137 -1.1174 TD [(Within)-372.1(this)-367.3(work,)-371.5(we)-372.9(did)-366.3(conrm)-371.7(and)-367.3(establish)-375.1(a)-370.9(useful)]TJ -1.0137 -1.1116 TD [(DKO)-190.2(model)-186.6(with)-184.1(a)-186.6(near)-191(1,000-fold)-186.2(difference)-188.5(in)-186.6(A2M)-183.6(plasma)]TJ T* [(protein)-297.1(expression)-301(levels.)-300.4(We)-293.6(initiated)-300.9(a)-296(successful)-302(study)-293.4(to)]TJ T* [(explore)-286.6(the)-286.8(PK/PD)-283.5(differences)-287.3(between)-288.7(wild-type)-283(and)-280.9(DKO)]TJ 0 -1.1174 TD [(mice.)-541.4(Comparable)-546.8(plasma)-540(C)]TJ 7.3823 0 0 6.5614 180.2834 339.9306 Tm (troughs)Tj 9.843 0 0 9.843 207.7795 341.5747 Tm [(between)-542.1(subsets)-544.1(were)]TJ -15.0386 -1.1116 TD [(observed)-252.8(with)-253.2(near)-254.4(dose)-247.3(proportional)-256.6(exposure)-252.8(for)-245.1(wild-type)]TJ T* [(and)-304(slightly)-302.9(less)-299.1(than)-305.2(dose)-299.1(proportional)-308.5(uptake)-302.8(for)-297(homozy-)]TJ 0 -1.1174 TD [(gous)-205.8(mice,)-213.1(which)-203.5(could)-208.4(be)-210.7(indicative)-205.1(of)-209.5(uptake)-204.9(differences)-212.4(to)]TJ 0 -1.1116 TD [(other)-196.8(compartments.)-201.2(ASO)-195(exposures)-196.1(in)-192.4(liver)-197(and)-194.5(kidney)-198(were)]TJ T* [(nearly)-291.3(overlapping)-291.1(for)-285.5(each)-290.1(tissue)-289.9(type)-287.9(in)-284.5(both)-286.8(sets)-287.5(of)-284.4(mice,)]TJ 0 -1.1174 TD [(with)-293.5(consistent)-289.8(kidney)-290.1(to)-284.6(liver)-289.1(ratios)-290(ranging)-291.2(from)]TJ /F9 1 Tf 20.6889 0 TD (*)Tj /F3 1 Tf .9964 0 TD .2897 Tc [(2t)289.7(o5)289.7(,)]TJ -21.6853 -1.1116 TD 0 Tc [(with)-472.1(dose)-471.9(proportional)-469.7(liver)-467.7(exposure)-471.7(and)-471(less)-471.8(than)-472.2(dose)]TJ T* [(proportional)-193.3(kidney)-186.5(exposure.)-187.1(Clearly)-189.8(a)-186.6(large)-186.5(amount)-187.7(of)-186.5(ASO)]TJ T* [(was)-247(distributed)-249.7(to)-244.2(the)-240.7(kidney,)-247.5(whereby)-247(transporter)-250.6(saturation)]TJ 0 -1.1174 TD [(at)-268.4(the)-269.5(higher)-272.8(dose)-264.6(range)-272.7(\(30)-268.2(and)-269.4(60)-163.5(mg/kg\))-272.9(may)-264.9(explain)-269.5(less)]TJ 0 -1.1116 TD [(than)-282.2(dose)-281.8(proportional)-285.4(uptake.)]TJ 26.5234 18.9264 TD [(From)-425.9(our)-435.2(study)-431.7(and)-430.7(from)-431.8(previous)-430.3(work,)-434.9(clearly)-431.9(tissue)]TJ -1.0137 -1.1116 TD [(exposure)-333.5(is)-336.2(the)-332.9(major)-336.3(driving)-330.5(force)-336.1(of)-336.2(ASO)-333.2(pharmacology,)]TJ 0 -1.1174 TD [(yet)-200.4(subcellular)-211.6(tissue)-203.5(exposure)-206.7(into)-200.5(productive)-209.4(compartments)]TJ 0 -1.1116 TD [(could)-358.1(be)-354.7(considered)-360(the)-355.9(ultimate)-358.5(inuencing)-359(factor)-354.6(driving)]TJ T* [(activity.)-349.1(Collectively,)-350.1(these)-347.6(phenomena)-354.5(have)-346.6(led)-350.2(to)-342.2(signi-)]TJ T* [(cant)-594.4(investment)-602.3(and)-592(heavy)-601.1(emphasis)-593.8(into)-597.9(synthetic)-599.9(ap-)]TJ 0 -1.1174 TD [(proaches)-686(to)-687.7(improve)-689.9(ASO)-684.5(backbone)-686.2(chem)-8(istry,)-682.9(which)]TJ 0 -1.1116 TD [(enhance)-329.1(tissue)-324.4(PK)-325.5(and)-327(improve)-327(PD)-331.2(activity)-328.4([35].)-324.6(Currently)]TJ T* [(underway)-438.2(are)-437.6(several)-437.3(ASO)-436.9(development)-443.3(programs,)-434.8(which)]TJ 0 -1.1174 TD [(emphasize)-240.4(receptor-specic)-243.3(mediated)-244.2(delivery.)-233.7(Trian)-8(tennary)]TJ /F7 1 Tf 0 -1.1116 TD (N)Tj /F3 1 Tf .6681 0 TD [(-acetylgalactosamine)-758.7(\(GalNAc)]TJ 7.3823 0 0 6.5614 444.4156 296.107 Tm (3)Tj 9.843 0 0 9.843 448.1573 297.7511 Tm [(\)-ASO)-750(conjugates)-751.8(have)]TJ -13.95 -1.1116 TD [(been)-450.2(used)-454.6(to)-451.6(specically)-454.5(target)-452.7(the)-453.8(asialoglycoprotein)-456.9(re-)]TJ 0 -1.1174 TD [(ceptor)-325.8(\(ASGPR\),)-330.3(which)-330.2(is)-330.4(highly)-329.4(expressed)-329.8(on)-324.7(hepatocytes)]TJ 0 -1.1116 TD [([36],)-301.5(offering)-303.8(a)-301.8(very)-299.3(effective)-308.5(uptake)-302.8(mechanism)-303.8(leading)-304(to)]TJ T* [(substantially)-281.8(enhanced)-284.2(clinical)-283.5(efcacies.)]TJ 1.0137 -1.1116 TD [(We)-385.8(looked)-393.8(at)-389.4(the)-390.5(effect)-396.1(of)-388.1(A2M)-391(knockout)-390.3(on)-388.1(the)-390.5(phar-)]TJ -1.0137 -1.1174 TD [(macological)-277.6(response)]TJ /F7 1 Tf 8.9621 0 TD [(in)-278.8(vivo)]TJ /F3 1 Tf 2.7359 0 TD [(,)-274.1(and)-275.2(based)-278.3(on)-272.9(our)-274(ndings,)-275.9(we)]TJ -11.698 -1.1116 TD [(suspect)-332.3(the)-327.1(presence)-335.8(of)-330.5(A2M)-327.6(contributes)-337.2(to)-324.9(increased)-337(shut-)]TJ T* [(tling)-426.3(of)-422.6(ASOs)-426.3(toward)-429.2(a)-422.7(more)-427.2(rapid)-421.5(endocytotic)-430.7(clearance)]TJ 0 -1.1174 TD [(pathway.)-504.1(By)-504.3(SRB1)-507.4(expression)-508.4(levels,)-507.8(a)-503.4(signicantly)-511(en-)]TJ 0 -1.1116 TD [(hanced)-407.5(efcacy)-409.6(was)-402.6(observed)-408.3(for)-406.4(homozygous)-404.9(mice,)-408.9(with)]TJ T* [(near)-582.7(twofold)-579(enhanced)-583.7(activities)-585.2(corresponding)-581(to)-578.3(EC)]TJ 7.3823 0 0 6.5614 542.551 175.5779 Tm (50)Tj 9.843 0 0 9.843 310.8472 166.2236 Tm [(values)-325.6(in)-324.9(the)-327.1(liver)-323.7(of)-330.5(roughly)-324.6(2.8)-322.4(and)-327(5.5)]TJ /F9 1 Tf 17.0775 0 TD (m)Tj /F3 1 Tf .5529 0 TD [(g/g)-326(for)-325.8(homozy-)]TJ -17.6305 -1.1116 TD [(gous)-292.2(and)-292.4(wild-type)-300.3(mice,)-293.7(respectively.)-297.9(Moreover,)-297.6(exploring)]TJ T* [(deeper)-292.3(into)-286.9(other)-294.7(tissues,)-288.4(the)-292.6(effect)-292.4(on)-290.2(SRB1)-288.5(expression)-295.3(be-)]TJ 0 -1.1174 TD [(tween)-446.6(other)-444.5(tissue)-445.4(types)-450.1(was)-442.9(less)-448.8(profound,)-444.2(yet)-448.1(a)-445.8(similar)]TJ 0 -1.1116 TD [(pattern)-252.2(is)-255.6(observed.)-256.3(Since)-249.7(SRB1)-254(expression)-260.7(is)-249.8(greatest)-254.2(in)-255.7(the)]TJ T* [(liver,)-332.9(it)-336.5(was)-333.4(not)-337.5(to)-336.4(our)-331.6(surprise)-338(that)-334.1(knockdown)-340.3(was)-333.5(not)-337.5(as)]TJ T* [(great)-278.6(in)-284.5(other)-283.2(tissues)-279.3(by)-278.7(single)-284.3(dose)-281.8(at)-280(the)-281.1(dose)-281.8(levels)-285.5(used.)]TJ 1.0137 -1.1174 TD [(As)-204.5(ASO)12.4(s)-214(bin)13.8(d)-214.2(t)0(o)-203.9(pla)12.7(sma)-207.1(pro)14(te)13.8(ins)-204.8(tig)13.7(htl)13.7(y)-214.2(\()]TJ /F8 1 Tf 16.4267 0 TD (>)Tj /F3 1 Tf .5472 0 TD [(90%)18.7(\),)-211.8(kno)14(cki)12.7(ng)]TJ -17.9876 -1.1116 TD [(out)-372.1(A2M)-379.5(cou)12.8(ld)-376.7(dir)13.9(ect)11.5(ly)-382.5(fac)11.7(ili)13.6(ta)13.8(te)-383.6(sub)14.2(cel)11.5(lul)13.7(ar)-377.7(upt)13.8(ake)-380(by)-376.6(re-)]TJ T* [(duc)12.8(ing)-418.1(the)-425.1(com)11.6(ple)12.7(x)-427.3(for)14(mat)11.5(ion)-423.9(off)14(eri)12.7(ng)-422.7(alt)12.6(ere)11.7(d)-433.1(upt)13.8(ake)-426.1(an)13.9(d)]TJ 0 -1.1174 TD [(int)13.7(ern)12.9(al)13.8(iza)11.5(tio)13.7(n)-496.4(pro)14(ces)11.8(ses)13.2(.)-498.8(T)0(h)13.9(ese)-489.3(bin)13.9(din)13.8(g)-496.4(dif)13.9(fer)12.9(enc)11.6(es)-492.7(cou)18.6(ld)]TJ ET q 1 i 94.791 732.245 m 514.942 732.245 l 514.942 479.225 l 94.791 479.225 l W n q 420.151 0 0 253.02 94.791 479.225 cm /Im4 Do Q Q BT /F5 1 Tf 9.845 0 0 9.845 59.7543 462.444 Tm [(FIG.)-250.4(4.)]TJ /F3 1 Tf 4.031 0 TD [(IHC)-252.4(staining)-251.3(of)-249.6(ASO)-252.1(in)-249.8(mouse)-254.7(liver)-248.3(depicting)-253.6(ION-353382)-253.4(uptake)-250.3(and)-251.8(retention.)-251.2(Mice)-254.9(were)-249(injected)-253.8(with)-252.8(both)-251.8(30)]TJ -4.031 -1.0135 TD [(and)-390(60)-163.2(mg/kg)-386.3(with)-385.2(evaluation)-388.2(at)-383.4(72)-169(h)-386.8(comparing)-386.9(both)-384.2(WT/WT)-386.1(and)-384.2(HO/HO)-388.5(type.)-388.7(ASO,)-382.1(antisense)-386.7(oligonucleotide;)-388.9(IHC,)]TJ T* (immunohistochemistry.)Tj ET 59.754 173.65 239.301 .22682 re f 59.754 86.343 239.301 .28348 re f 59.754 135.042 239.301 .22678 re f BT /F6 1 Tf 9.845 0 0 9.845 63.7228 189.2976 Tm (Table)Tj /F3 1 Tf 3.0002 0 TD (3.)Tj /F6 1 Tf 1.2496 0 TD [(Total)-334(Plasma)-334.5(Protein)-330.4(Binding)-338.5(as)-329.9(Percent)]TJ -2.3552 -1.0135 TD [(Protein)-330.4(Bound)-336.2(Antisense)-340.1(Oligonucleotide)]TJ /F7 1 Tf -2.2977 -2.8562 TD (Plasma)Tj 0 -1.0077 TD (subset)Tj 5.1539 2.0212 TD (Concentration)Tj -.19 -1.0135 TD [(of)-336.2(ION-353382)]TJ 1.4512 -1.0077 TD (\()Tj /F9 1 Tf .334 0 TD (m)Tj /F7 1 Tf .5471 0 TD (g/mL\))Tj 5.9486 2.0212 TD (Number)Tj -.5528 -1.0135 TD [(of)-330.4(samples)]TJ 1.5778 -1.0077 TD (\()Tj /F3 1 Tf .334 0 TD (n)Tj /F7 1 Tf .501 0 TD (\))Tj 4.7796 2.0212 TD (Percent)Tj -1.3072 -1.0135 TD [(protein)-336.5(bound)]TJ .3167 -1.0077 TD [(\(%\),)-335.6(\()]TJ /F13 1 Tf 2.3437 .0058 TD ()Tj /F7 1 Tf -.023 -.0058 TD (x)Tj /F8 1 Tf .6104 0 TD ()Tj /F9 1 Tf .7198 0 TD (s)Tj /F7 1 Tf .668 0 TD (x\))Tj /F3 1 Tf -23.2127 -1.9003 TD [(WT/WT)-4895(5)-5805.6(3)-4400.5(98.4)]TJ /F8 1 Tf 21.416 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.01)Tj -22.1358 -1.0135 TD [(WT/WT)-3893(150)-5807.6(3)-4400.5(98.3)]TJ /F8 1 Tf 21.416 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.09)Tj -22.1358 -1.0077 TD [(HO/HO)-5145(5)-5805.6(3)-4400.5(98.5)]TJ /F8 1 Tf 21.416 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.14)Tj -22.1358 -1.0135 TD [(HO/HO)-4143(150)-5807.6(3)-3899.5(98.04)]TJ /F8 1 Tf 21.416 0 TD ()Tj /F3 1 Tf .7198 0 TD (0.21)Tj 8.7511 0 0 8.7511 67.748 74.5512 Tm [(Ultracentrifugation)-569(using)-574.4(a)-570.1(30K)-568.9(molecular)-569.7(weight)-570.5(lter)-574.3(with)]TJ -.9134 -1.0236 TD [(ECL-ELISA)-448.6(was)-445.3(used.)-438.1(Recovery)-448.7(was)-445.3(determined)-445.4(to)-443.4(be)-439.4(98.6%)]TJ /F8 1 Tf 26.6261 0 TD ()Tj /F3 1 Tf -26.6261 -1.0236 TD [(0.08%)-332.3(\()]TJ /F7 1 Tf 3.2521 0 TD (n)Tj /F8 1 Tf .6673 0 TD (=)Tj /F3 1 Tf .7126 0 TD (3\).)Tj /F4 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(PK/PD)-340.1(OF)-331.2(ION-353382,)-332.4(A)-337.9(MODEL)-333.5(ASO:)-334.7(IN)-335.1(WT)-335.9(AND)-330.9(DKO)-337.5(MICE)-23255.2(231)]TJ ET endstream endobj 123 0 obj <>stream Adobed       k  s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjzm!1AQa"q2#BRbr3$4CS%cs5DT &6E'dtU7()󄔤euFVfvGWgw8HXhx9IYiy*:JZjz?^yl׌7;Oadh0|/񦿫- ;wN(0I߮Imb[yA<6bw[kݭ8d:+w3"${۱{Ym.b%C֧|űgsFM` kSgy$ɡ'L$1SS(ٶ[bF!vyӭ}XcS0n_Fme)m>!y6ݝ܊lOnơ[w S]:'5s)=C㆚}Ƣ¥e]Iܑ^مnןt=BH5=6%ua*gpfѱzڞ9_O}`fhGoeONmS@VѾ##Ive%=XcaU1 2AN-]ͩaAk<0I;-S2Z$lfOjk .vPo rXmBM6! dZ7-OMu2y({]#`0Y }؊OvA({݆(t+#d]Giv,6)O7bկQH݂xmĒ#34 ;;ɭ 8flwc!a[A}o#<ƥFVvQ<v*t#I׍;rpE5Nh=Lw)gb6sZ}wě)Ai`7v7Idu-, $1t#$!PQ̚y>+?d%J`Ճ(m9zY*<6j.)tueiđ}%غ?޺F"Ih*F 2 Rm%(,`#:8>?,d 7WtǪXb+5=Tvix006*E/~7`?+~SzR׮yeQPJ 2_ l'. * pqEi0:;%7:TT4*aSΝMVk fJtpsM#-F%[YVRje;b:Teha,`T0#S}{ H;0d eii%T!zVtww.ާwyTl̄(2[%ghf@I),R~N;T)jݗc[$˴e[])y$hF(OS2eCY9-dp92p,r6v~bh*sҧ#>l?"W0$ ֵ?<*ׅIo*zuɉE3<r/t=V'H Vb9~=X &Zt7m=akM7Ze#ف﫰H$}yF; e\hЕ ,VQ*~#]ÚW%EذpCE z{d9lw`mn^9&PGЌc2̩bE&c6ĚvK f<%d.sX ˰-q#rH}ܱv*.킞L [a<A#e^? n:Sðw)U5ɘ;4ynvMrXةC"50Z]Mp#:(L S SV2c4m`7LN] re+\݈H=iù#%z/d o9Ұ y{l$ezvtoSJ:#"R:i7A_Tv bD\ APı9_eAzU,o\K23vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWa4ny cIL (d&~]u)uip_f\h1oQX)vMw~r(@l:f,rwjZ# ڙVvE<˕pdr$DW9O,dxE,2M(_ݡ'};.iւ(&J0v̭ggDm7#9IAZW'zm~*v4m6uR&DS\x۰?.@Ve@OD%X$;4VXKi:~TqvJvwQ^NZ]bSؕ_|4B5;R;W!n9D`MH>e";Dڛ-%P1&#vf&kgZAh‡W8 J7E&6r?g:.8a Mr++C@kl7)P9}Db2ejai+S_lZy v"Ex6S˚Ǔqm3HD1Lu.B,fDEdG`6WŶ.eQC7 Q?OafGɲ@䵛vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUHBnH-,+9^+v'hN1$AU9Uz "I@.Oͼ~zࢴV\ݜ K ZQAVl[6@zG(b7cE<uՋ[i1ȿ_` ʵ-EqW[\қoMz[g[92F҃q96ꥄ>qE{m "f5jʛeg#6Ӓ?r7\\;jF\LJq;#鮵"$VEȩ L5b&g?(mڿpO%RC+ΌO"ܿ VN"zͺX%W" $kA+t;$)M[t8QdIu/Ǒ{ftp3kϓz(*hҔ〬תjYx͛hJ69H(n5;tkk+72Z霌9u 1O3ZC *,[+"ES}efQ,e45# o)7CJoVhVH^UBP@dx[5Xܤ[z W@˺-m[LMK/zerDIxւ"?0|KMa4=i!.I{7ϧh˖\k d%v(+S_*g> tM$Qzm+hq䳇6jh [&d DSOLr~%=J[[U$qJ"7gnaD*lӆ@ ӰJF!ihGl@%hR>3J=*wj6vh^T|ݐM:|ly{d !;e[̊Pm16$W4EصLcpuF F%{H(dxǖ%hjo0>9[.bYT)QTNǙbzAu=NDA#NX̎ H D[nM";@0рDŽ6,>LQWqLqG-TM:Ҕ=|+< 7a^jVe&a+aռޔт(+#v'b`BlRɧ1,:wn;;9 =@@)ȝN?ܞ[=)"!v߱F`K[/ș{bڲMH96Љxqb0sRt\9-f]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vGn)lQlOi0"5Zn]I eZ׶@ lZ*H.] >=XYԌTj|}T'Ӎ$0ZLZ*ji֭^ XWs]f(ƈn;ND 7k)f,蹦7md#_RhߙyQ4&ø64Nsɮ9IGE$k\9?a@%2*7Bǩ9G&D;9x"'7K6h[vͺ!`aM7`xut cO7g`=@9N[ԩF;5i.mhz3w qՒmD*#,S!W꫅y(,JqKiؒQu(E*I14mWGU[4 *; .1m86Qd2Bz~9)NG +I;#[E %}j=^(SZab.3FiQDf=5q#qM2XK!HR3;$8hGn9g#!W>>T}ɧ^ꯦYFxOa 3~h^?,Sڜz[0*,ݏ][LMDH eN]O<05ZX%ðM4 $;&.­r88? i1N]D4=V v$G4J49 ~h?U`VsFj)L܎Ƹݠ%h>e'pR.C=s]KP[!!F<2(&{L Xq W\O2 W>z',ͧ KMii,^ZJL6ff!ʓW0`ؒrޛ?F@e`Ez-?$*Dk>sOO} ]FB((>l3f""I*TfH68DSų"YomY𪑷߀xi ~H‡|QA[Z6Kp=~̌:py9 P=c]v>\crD.hL.-`Yī+-h(uv$<#e@sddGG<^G~<N0BKA,mGciA gvGSK2W̝nyRW>4csb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊"7-*WƽNN$ yŔjO`\F:P#H{;H{yQdsvN'eFOC"(2^&e\6vF.uȹ&HjgC9C^ż0]M$gq99#)nY"<ǥOHR.Cd7)h>H՜\ZoV= !'e!bgi컉T"حw ]YnxPrU38Z<# 0t۩ʼ\e`YRH n/M"'+T.%hຖsjQ.'cmaK[- ikJOzI`0hU)0}zW͗7a\quAzǦԫwl0 Ȇi֯=Ӥ&jF)4'-r1ח37O+ sr gtVXQDwn;[=Bx1098MVd`J5lA/yWK`!Yddf"Ș_>m7{w2N#Hũ&{%d\QVȜg!pK;7E9.7pfV0##û8RҢ"G/yiejYѵkpg?h}9~YG]#oԡA{oߏ9s# k`fR Ќ̖kZ"P@GLb''r}zm̫ #PѼė>T}6s É#j%NKy6!sCU?HW3V~9`O H#~gV1cڵ d]=r).ZĂM`dP= C3v2V3[>nHlG1yp%:dcͿs^bxy6)]g)a[<'4#:\c 4R;6O[ 4RZ$z c`Cr+c7q 휌!V&RzW%vn\YQ@v:%%wb$(,ܚO^>>!ven)*W_db$8 l2Pj.j,rF|=;xdDW kfTdbhFȥ0yZ~6x{c[;ۅ(Y>C>b%i8h!#2fW'av4nG!ӱSHA5ˣhRIA G\1$Hb:&De&W +ww</9l?<(.ħ m2(đ/jHz7ƬAj2HB=Nqi¨0PT [`vȥٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]H/5X܁R*`O0a4}ӟN\UV3ysT:뀭(%ln\f Q7Qb4E{T/=v9_ӝN!; QHS\!;JM,$9$+(vEuf?}v)Dwg_or-g(׿4ux'~IMqrhIЪ7~nj4Os<ğHTTY?rik}uj6DVywCf[lǖ?RJA?>]2vd-k>4@W۠axbeEF#cT܍NϦFU(}vY}n,YPCY;Y#k؊MNGrt9-q]ڂ(GVȐy.1*2YpH>$1 X6;I [0[?,c][% ޸&྾vK'-)ҙc‡{d=GE<͚K&vdMq*>y&h:dr; f?Tiq=ώٵd4;d܎Ǣ3qHPoF;w2*}V;P!!cd.伄zH$ Ba)vk*ܚ-N‹i^_MPN[^+v$pAndIE;\k˪́SF¹HL@gҦ$\jj@achZ{lINA W&ª\$/ H 2F t金YBޕ5ȩbSQ(l)%!|/0jڄ'wgP7]MfdMEyWu |k]Ine5uK[>Qf2mPpwu[CZSFhbwo+r>RB#Ku%7|3*8O Xu.W Ȑ$^a7o/=i"6DfDuluM7Xk[wG"_fa[ؼ/ Pr7`SX-S^Wmrks[-x=jro*[x!)ڀ1RpGlj泣FTuƙfzɈZPȀJH`}BӑE 1uJnǓA5RTvO_9H sv9wUEY*A[~`;t4\١tٛ202۹>HRb%"!@C^G'-晬H\G0U[x͊XKb.@:ݬzq0\sMɬߜ3[s9)>`vog^D˫i,Jaixzt&k ֙ʴQo0 qe;6ٱv) DAe|qͯx^wh (3n_Tqu%e"Ÿ)V/͞5 <d¡wɆ\(}z?kdف4]}5gV<(ŠJ( xc-bsdfML ]ş@uٗDGZrpnጅӲ(:,sl*Nma(5Qaց-6F6Ҹ$H=NY9iz1$N[\dvv$^FSf'mQ:XM˟'bnR2)`>2[ܫ96o|bAP0Rr1 vӤڻpn,۹dvv0XtGWm%3K+((] nO#eB[$;"^- ҦRj;];9G4y$kbH =i\թ^&=2C'^ڕXsfxmݚr57Th`G6fECuoĒEu4ʡ %eqwq[F Nz mnHc#B(rG4 v2-#jzl7SE6?G NƝB̻SEKF Wv@;`} ILΟ{ P.j)e4C^NJdq`"rv эs= UƹT^Psvem͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*me+k"{s^Nd*'E Tz).m4&%Pc]NYP#[,]^HA*:h<3F[L3+e-V@NveJ2ys_]SVP" fi. -y'C3Mo#TR{<.Mg->|2FxM%iUxb"Hdz\GFCfl}VJEGȤfE Rz|~JCVיmZc lG4PT\v.%c;0kui]PhPDhgYa㏤\^)QR_LְڃHa%VujxTb; 9\'b2 )&W{G/p| 9mc h] r P d%Z bLWiyWd7~sZ^KAر$`>6rJ+M/;ijs'؍ze٭ Q¬@XV216;#0)!MFzEGnm3L3sx7}.וrlv[Nנ UvŢ1#=2;@˳^QganS IvIW\[1ÈjCdL+%BE?6ݍ>2FK,{ 濢-ҹAuW  a;"bU0w$gDĻrPyԖ5ڝ)G:;loS?j:}_GJm2j2XvjLְFvB(T ƁK#MS[Pdq̄۲+zEō.w ۓM.y5^zrs]}A񐲉]-t#NQJ=YJN:RKШ'vv Vv HG`FDy- o-nMv&|b-2~c  VGpi;i֑^xrJӾJY9nU+h-c w3P7a/PO ջՒ||gbԴ1[04"ʦ3g08>ѺiKy}خ?)mOOMWJsQzdwc׽ @5r]jмQM"$XQ"owMh:u3y~b{IS|Z1DCf xo@ӧ$/]=CB)Jg@*˰GUb;xͤìmyZ夺{J3da'l ^Sɽ6wL2lNȆBv.ɪqAĐa[c^DHbEG@8<3${j[ȀYnN]M#gN1;}HNRb5CKɿ<]ȡ V ca5#efFGQ2&6~1E@aܗG1:n0.͂XHT`G\x-ûkm`KDHF* QP)Cƞ8%%.*ÐXdJC L&h1&܎9@=O7kqLVg 4Lů8Gv YE>d˂JF`mV͓y>s4m_FI pѩcUQڔ^t\ت򶓭^O;H⸰7K>> UJ"W)kHTjuzثCƬJ2 _=|تءS(Fe惧9U^I+zlkOȌTz8vlتw׺N}y͝:4l7ګfRmrzDr)@T͊k+ Z E9(Ê7ccZ+4N rU&*B1@nS7Uu@nu:SEBR?QPު:RY-#9$9A1;)TT~i\嬎<0<3WeO~vkw HXdj8V5/Srz.=:zdgMbA&F1Dl&иȾ 1yv#"̧=%h>n hWєQ(XWöWVT`vyʲV(ɓAsqH/"%x~*M|ad'N|i.n,ybc`TR6b)<3bǩilXKJ{zH6XUcTt$:7KG4 QĬX!溆fJ*1cVwbPb^㑌uV vť-̀Hh؏cL"ݜ#7ךFwdZ wSœc;s*գĻCnr{ytpBݧz|_ 1ÄY2;tm{%\ n\j{gG>UkvAu 졃H :ww:ku$٢VDHmI4eI$0ޛW۰!~zS΋-D!4n`+ D(ekK;7IЎqea<6/F~ aJ$I;f3Z[$ίK0cD96-% ր4Hq_Gfnm$ϋ;'QGy;mo"F|kmClY>"&[1M-oNT7&uN4ޙBrp06kK2ƒ 今t9E-a@FE*db?k6Q 5L͕7w7RzdzPzՠL/m Gn?d>miĭrQɯf{xՀsI(zl7D%Pxge#NaNnEEۈNQ]g&GAv%e NI%Aco y(.n.x8om Sƹdw +KD!Jzeb$]I7¿HqCޑ}z7`e0O)ሴHȮHZh^9- $.H M3;Uٲ#kY"vԴ@Zzwj88c4PKHbF*8$))c|&` k+@ 0 4!#eR67qgk}i0Y.I<AE%̅V^ʢ6bqm+,l"02vru+qNFѽ5gbhis廸^]j*1qP:;cںȈG L^^ }|rk3-ZvXY 9bWY/D03bwYbմ:_ador &*ʻ ثsV^t/C~]Xu;+ B^(w ͊4O:,-/0"u=r;yʵt_>Ic[Y H٠ 9&ԐՉث 4*ʳiii6o"G,S emմO5\Z-kZhԚX$\C[a>tA\تia.P-,4RJ$+X(>v LU]K[)hޢ2~ IQb]_ז$w7LnXcX2[?\ƥ$ 1xԸ6dTfeO˛8NK7j6_YObLOaJʐckZhֶY\nfZ (|iPgѱX֛1JpץlҳuSE ki,w2Ĥ/Uj1&dXݾ5:H.Lՠea+eӗ cVe巵e-,ڽ27ՌA[ U最~9}A~bh|F}K]s?OM1ٺr 4j"kۜ۟etќ`ʚ,m<G}s[q,-I3P3KXwmsx׏jɶo[PaC=Oߩ=횘nm9_o)ckAvRT7g06=vEiGmJPeg*j㒏-y4[ЕJ㘺l挰̾U|zH;CMBѮIpm Fga*qxE|Aj"g jOn&(k9vsb =^?kw y1rwj=iÏ)JWIʭ(skRMΣsKy UXujf"&bܭ$vn! nGS{H9AߓS[RY9[01Gt}協6Ev\XKnГ&-5Hm^UA[xR+ 8 SLGWe^֠+H游K`E6`;aogd[3HW̱);b oJnrG NHڒz}u{H-ȶ&_ߛzlBy5acQͷo:ޫi*1HqB3,|(rgvKd{& TԚoLveٯJ̅Ox݁-\* /o-92 *!Lj͑`wIZTtNS:6F.\jO1Hn'f.)HݜcCw`C[ 4љ4fL%.`̉s:޸-PwpgҘ ##t]2L<||H'1vy;=QWZ?QZf1nQq闒ij(ȑJ %v90D)U.$9!2?]I[G40[zq9K8Uc }\/*b§NX&{a ZAe`dxl8d[Y`kvIcx΀*3cX(&c5/A1ʘv }oluמ0bZ&<51N 1 &c9lqmk%lVsȻ!ǙmRc2>mx6W`@5ucH M6-ˏ2CXc}Nk-3rدJtu8DNȁdŁYiF6]0m֢*H܊r94MsO7b:+m"ZJ%v)[͵T+˝vmzF ,`r+2a?WA$e[9c]A- WFe*vnTB#Uُ]r0y;"6#GQ+eQ1ڠq_ tHv'IbbHG-[ګȀ:wbzT~d=0݊A b:G^ksO{b,.Co}>] L9M};1FPO;(jP*6Hܢ@w"@t?K[Ht`D th2)&59"VP+AYD}D!"NGurҳ\F#9KBd%*+\I4AY*Ƕ8t_O560?1#fXR{hY=lw_XoV֑SoL̀>H&&]m$r%yp1P54LY8n7OnFLhvOKDQ$;8wW濛u=^ӡIfZ$qwgK(' ͍9^r\0HSُn#Ĝ>yj)L[N3 ?9NSN3k)xmv+>܉gI s~1n2O>y;MՎwkw >\GR4J[A?\1u}Y??wE}6L5ZkO-Zݡc^FI^_XzS;X1VgJi;[G)C4YiC\-Zuvm͊6*ثb-_Mӵ:aèFQՍHYobflUٱWf]vlU1OoZYJFť⢆:SOtE$pvNsL n3Bkdֵ뤺ծhFݔv$e1t #uK0":v%{u5kH$WǢ=!1v/Q$ב-K4܃"I.2ji+[M EO O$cF= ލoy{y cmĻЖH'zc~[' ”.Z.i&IGz2|A˱ʃ7vkخ3p"FiNqBUVvyKMGG|RΦ9~ dcb[mTd} \ B ZHIoaBǒ`{ͷRwXLÄ RAszqhf3֤zGqr =zoy0q6e*$~>Vݶt-pgoI ɕYV$^ f92+r5GD&pִ'MKʽdWkv ЩYI؏PLq"Ʊ8=(XI]vƝ$Њ6B[\Zi:j,ĴĂ?&Ԁ骯&ݑ4NSuefeʢbXDu7cj?WƲ#!G WnlGd*Տ~S+q6:ezJ 6c0 H rI(i;"5'O,z|21bxE@xQ1At:֧Njb([\Z ~:9SwQ%1,a ne;;Q7@4DkK]1̑r_+N<݂fe`8ib%i;v.ռ~@61]oe/sTMF5yVxSYX),8)m` Fe#OA=]O()a R@v(ԂvSSⴻդH+2eC_W`VKM;K*ȰFTU>Y8qK鈶U\˱?-Ti-}Î5 ~n"?/Q[y%6m](Y7FgbUNdDqm葲Ljgc?J[M k9ǖ~8OPu,ƴI3"5ڸz"ݍƒS bLVn1" H5?/}R `.<%lAU PgBݛ,Cē铰vbnvb.*J(lb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊#PE]rQS2\Hvpk6Sh@SáJB1dWk["JCG `/4N .B;xM9'\I6$@xTy=lGK{kz!E0cgd]5FGg > 0TEQN rW!䃕%tW*h9i'\iV*v4w`:nMWkZ~I;F#h1>;؅(ٺtƷW`H8Z#ֆxH{rѭ߄j9 IV4o^JT /T8, #4݁9r8lz1n;TE85ߗZn"6@qjt4ͦwKx(4)p[NYN6ƝMJ.Mt0uTH8٢+P P)Bk^Yjcņ^MWNEP);tqDG@mL.j(Ӊ?d MCćϝECC GH%nx,::asn[NHnh)#`dm،!f$Tb7 jv fcf8 Ly$۳\Io3Ee EGE2O/;@zoL&7a) >AtcЃ@ds1[!_L$RE5V:מm~.l*:dcEgۤڃjO9`tF°ˋ*nvlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWgT]k麍;f6.faTyˡ_Ci+ۚΏrF}ȡ|]-<%M#-Yqeh,z rǓ1"5ޟ$K.`mj%&#r-. ~?U`O.1 ٜ{ TR1:&5a>9!VPk#>y"D4[ƃJ8NCFI\5޵ڙZ ?YĀ雙 k湨P3Ϡڟ<~Rt<\ޛSzsND%aasj;zą(ecXU;}9jǴj72V`slHIu3麣]-`9tRDn_t[qJK5EH+m:ºmrڐ(eFv6~97-ҽtH<|b:W71طm`D8`\UN|WSy Tw`bUCBq,2(1!eIm qxIv/hmhJK4;!~q5 &g%Z>Om1cK<.Įoኮ=WFXnE/?RENAyrc@>y0Ei0:'nRuShp[vQ;e$" H`:PtDnӨ yʲ 'G$]ߓ^fԬPP: 6,&"oVD#0hPʞL:d ${gb7.iڣ'τGuK]KQ7UTX㌞F)V>''نfs}Z,'Ci I4MĬ+f58B\q]_CQCs}b#ZG=ώ=8.(JM {d4LUJIᚎ F?|[oZR$hƬ{㘫,*(Xll{H.+(HPFjd @5䪱1$W J}a=XUH3 c >cRtpdgiG#=1%Ze]ٰPGYibaIaiE:&؈GVIk ]0qzb^|ҔSI;8D^[Xd0Z'"ţ;i;\MYgڀ4QMda~yd*v x1{w`kh̊`qrr;_HwQOGa]#;Yŏrr$<֢}B;edojNؤ)rv%{iu>>Tc`yn' s'=,LYo#R"<2xKNhѺlՠ=r-h05vYMty\AgyǨm켹*6:pRn?olsm髵¿do3m$GQq++Zmlփж? I99gϔp"1X疼.:յ|xYЌvz];c E[Q +ȑa2`]fcVcԓ4m೑'H @$)5j}?~CwIcpnsc@>N{6&siWR]ښ5?H:qF&ŬAxfe ܃޹ h [ !O,W!!<#3 !MH>b/t<*-ݚe@481L}6]p=yo bX*% й6z]]cVAUѺP ̸`+kKt[Po1 @] Yp_WaP6~}sJ2C˨E|snlfYWj}G62v r|iWef1ؐCQ!o@G\+~wbm{muh6DRPv@w6_jubp42rأ4)s)SCc<ͨ]iogQ4x4#ɢwKpn}4B:3%(lvvvGi5 JQ+Qz@ql2ݒ/.{ӤG+1)FCN892lJ40= gmc<`^]<0˚bMHeyL!#LKG܃_LA@D1'dEC-dR IW<8J2aLZii}"@r!Swͯ.=B/ܵiJ6ˉ='^uT;+MX&Zж0!7t€gEb1j3E+7G[8q&݂nۭPF"!vX#&{̭N,&Rin;/UNXgggu,\ǣGb5R\'!@4d Hw=yF+KJ;8d=Õ  x\~o| gdz4PcNvf\2բY4%EFjh[rkqrW =@5k#t\aO%!:dHrp۰WNTy3v1|<<{ƸWcPMqD)ޘIv6kamf~.]k$^N6?*_H2]hR LHv3Ycu))cE2xT@6v$]"$m5IKR-`Vߦ,͓,sz+(T'Mo=BO{ۧXݍ!?zǛk^Z2;%F&M6F+/T/|O{r:j0x:t2hƴb[H.s"AM15L) m BcR8d5(ivVvp>̈>t#Ssb;_˾^ŎG%"" 84FlU/if)Eİ['C+t=lUmn.lKxnZxwD%Փ++K*M FְHR=sb7ιZNMJi"aZ?kfP7I-ŧ(dWG{y&^q-j2(<ت0ٛ*e[k'YRȌҺSWۮlU/|$ְ=ךDƬo =a!Zت/!y 深- eYܘcf(nlU3]Q򦣥E'U_SyQ %ȂNLb@r=sbzב= j<ޥ.akS4h'&IU6*b͊6*ثy;Y%Τ-5->Xa^Ic1#4cЦ:PKi|/(\4F 0}-Lgy%)؎̨9ǚ]uX3MmBAƿd8\Tc sbAtZ}Ҵ7;9+ EBĒe^C{}+R44 N\!$mj…ބK}VSOCӅTi8W'8/uj7wBYC"($zF':[=P֕f8 O4*ODV!P<2|Hv;LHtԏ&cZH:qrfߋS2ÆwA-/PXJ 6H4Gu`èdG򿗴-MXڙϬ'h94I$jNe 3kffoڸAjettWO*9DݍMdq(j}01[(s]_ɯZgtu0#ToOfεUVQͯWO!FFu+VٚJG"$- erri$^`=qOaOyBFA,w\)HEwȓI;?Xn&mA{&؍ζt-l#w sfYτso/m^3@xKXw,Ց?q'0HT:9շCJzPBC;Tw-c&29$dւ0EHP4K$kZlp$//D$'Ѩa8c->YE9UO2EhwpH2w65KVܝD. 4a-+i'](*)'nwt]a jҾ!ؕlMk;RϚvJVX4#u2!KKZı#|El=م92,nE.7S)5-Ǡb]RTt<4bN0DP & tF 'aEƠ!~b۰xNTbAd4 ЁFo ӱ;ƌU:lof sv#j"NΣ% v.#Xk}M7SI!Qꑹo|?s;9)izQܓ0˾]Kyla>I|8Uɑkjk^仿ѾaFEя%<TSR[nwW'7&yt:k!'*F@[cs~ x]Ʉэ6xCFp+A{kzڀÉa‡휤%*@_|ԃЯQܳ r@z-dvS%;K]{M1u6]ߘ VY &Q"5bVpF0Zsf=Ŝ%\a% *|J;)LlΛm XZ% (.ncIaA );،OjJ{W$#h#K'7L]QE &;(.wV1H|{丬 .M2 ;"&H;"znkAR7ࣩ>ţ09ȌEY rsfdOIƗa3 -s vQ |o??$avb'5tjPdocu-RkH,W֞Rcqu#\o;vGe_o ~]&]ZGUtha foIGY:fϔk- Jws+$W*%1gwu^4v$r1e퓓, zߜl.<N. ReV {qd:fYM懓/5yInM?ICZ\Zq $>,ROBXKjz2Z8MFMkp<7celU57&̗[_9 WFm: X^RH ߺ)E%N[fR(~eyKA4fcP_^TK9sF̫F|ت,bKAuyvGWRXUxrbj14SU$!NU4H8Z1hXI(LR2 @>wV=X g0Gis :PcZw͊2<1Au}"XhЮ.k*Q1޲VxJShO2KX`AZ%<ϫP)MY~i}pjOV^pnAqrJ6*kqZ-+}_CPO#XmndO'F乱TW?2|ysF4[-NSUYW0lK齸A49T̾r/]CRnkum{(/$K=-#NlU癱Wf]vlUԭ73vH7*ċ[=]P !I0Shz֗qpzw3s LjQ\áY+j5n8S:mc d8KT8U#DUe=G'wWRu$RfPz3ʄ6ԜIt@r|Y, 5N[bt.2jEml~a"{OҼZSژϜb^1#7l#ه$JͲ2M}k0hG:e=_NĒ;1+GG$nZyKtPƓQ5ʣ"El&&E,FLjqD+*[t8Mb ηvv<c*ӣf09H"bBAl0DdQHdQl R槇1AEiHv\")H*k#-c1b(d14:u$ 0$3'1k. &5I0qȧe/e1F.*A9$Z/kbiNš0Jop,RHp:* LR|uvF<,H( r!ׯZE݂,, |EXQWmUb,SGr_[vG:d3_G*rjƒot˧";di.-.Ⱥ *se̖™A-b&]* zЩ\]LsB<fpC\8nshTS)LgлOs{39'&(;WuGv]}̱]e9rTZ"HwrͿU&Y'e|4jrn`F8 ,:F**Y \JcR~@J; n-|R}F~yYٺ3A_*{Ҙ}i+Mq0 rP{0QݨzYiͬڊV/&5j>y2 yn ־Y5ٵAJcHQ3,l3 C#Aۦ)srDoN1=6`%f3LTKybOPS`vHUR'`ƹf9$ hrY.7BvP:R\S'bצi =)oNCS+ vdi5nɁ&#)KF*(U)ZWN,$]/jRqړ^^O eӓ1/2?9+5=?[\*\ Q5qK$7g H zb5_u yI29kVMΠ &D`NghpcuWg ·2s%I e*iJ %*q7w^Э;jY:$gPnad^$v`p7BR'f ֻצu}:{Ky*Xw5az[ld!dc$~ei:vHRKU:Tu=qpHlJӾB˛)#dhRn+S\d6xqU)/#jP\Oj.DI7fo(#>)ѥXĖEjrnTNaa%66ʒ]d7w=Ke$PC_(,84Xܓ)p{m6#~CPCr~`h=*2Od@E$Lt;~nx[{}FH3lC7jwnm u($v囎dn}A6/=3G >kտ\ZTلw ZS}I ~_ZI*]IP/\iPb7p[,gPlΑZ=J#kE޵=Q 246{ʹF"v?}`jq!ᑇN)@J)vY[F2aePdlz sX Q$NUѮ˟TaꕌIN&-(T]dd+r۲5X+<>q̼RgTx"RTAaocr3RNsD x"H#q`z`.«#&r#sH%]m(I$U"^lʋlA(*FOPY1 1e wvn"e?_lňca7%*^&#v# D04I ܉AE>wn&Jr{e3;lz`{@@(WN&11ޚyNYXڂLLz@5^t&d")>tt5-~LnC\-3+MGr_lz50n,#em ̬ziK9L$E 1hot]ᐊo&9#<ݏNo -yI!xNa`)畮6ۊmktγ,\f(w k(boF<] =mX%MN4͌,4ow`dekKhq琎]K9v[de6I fm2)#,^ ;݁ndiiGϾN,yg]ݿ]፭nH;-z,N/w{S4hn;WUՂE,fGNP mPR:u՝>r7w(ًcaryjdgQ'|d [c-rʓ7эEEz5ޞq$8?g2S\@HNʆ+WmI>h9z)E`Vl$o, n*N<}]HiqzF6_ho{%Ml0#jvs[p"ь֯(bw&3 zȣ׹ÜGk)]igA@z|NkuݩÇ̷cZƍj$nNvLsdG{ZT2lض)vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWaq4Q#VsN8ĂKe-A(h:·Oq_7$4o_4};֒dMXmvX>m&% @y*H u*{06[;/MxcZfAlH^36ב52j|jXN#dYk@ۘU2ѣ)=}q4 )WWwbajG(&~c,CICp=J銓ӮNݜzvNjX6\Ti/eiy=˄0cȢ._v֗9:G# 杜]Bjܗ|<'4$c,&%ҙ=fmo'I166yĦ5^P, A/ GHq`v3yhүN/@%t39Ӌ_ωJՒ+Z)h3YƩ[ŭO"oRݷo&~UX^MWQYʬʌ,j79 cˆ}]DXht>¬yS%yx_c{W~Zf &9&H-,hw?Du+MSqojL{=6Cڤdhڗdj<ã+yZQ: 8zF@.}KHHKf{~AW ʰ$h,06ZO[䑂jky>3{W~L׬tM^ݭ k)>W'#n Jرvo3`ou?&3jKKN6v_#;/+G!wKGȣG21MNPmm#hoi%w;cٮfįJ'i2TRH}]Qdԝ݆1FoKR1|5ȳvE|d5x! "^O,(\eagab=8j~lƞSVyDU;*McS1#NJoLH(PJ[ |YkԨBiR|1FFȲU!L-5ZNN1\i|EzTҸ.^̯**Hez5L;5ʒjHE-V<"QJ|@-<1Z9pbfFU4sFW{8L_˹Εmt85hKr8uI&ҙeydi՛ë[1/S#nu,VznyƧ~d۱ئemriu ʱ$|hGv` + n"ח H-ũ`tAd8oX2ZXG;aX^/\:-/g,z0EFV,+5ZO܈n B[;1u)chQDi s} lG<҈5ٍ4*؝Y ƱQӮ伂0UrrIC ؓfu{-OAۦȄ)9HP-jPTݲ<;/e 9|v3"*VSd+(t.W@OFGJe6H':`N8BE_HSY٬ڿu{R kdXlt핝)sfD1BaVeHdCנӒ-H#\q%{Lq"ĝCT'c'K;B8 #LښSy\򝕏#XfMK$ɖxzfsN[)i7*zd7Q]iS$񻒎fD&$edb mb9楦7&rшk$*6m:>8Ɩ|.a xOF2ujWd+Q%6$f6>&"M- #Phʮwv>)y}Hu_$vխ^8x 嘠o} J=L"!%oo_-9rkdBԪv4rN\W7,++ph@9v9@DcocfxL|)֧ 1*A;vv)o97{rP˄`ҫomBǸʉgeHknm+Q*77mպDa!mk-^83tzb$+7aJ\]=h~|&6)'vO|(Z~4޹Hn[oHՒS!>3!ӬϸnA$Nb!@r us|H!^EN]XvD?.6zՓ(kz8wfdMx3#tE͡8WG 4~c&z5̰ˆEX7tnuVhX]"K;iUv3I ¹Ta].!ni$tR+zHvq$HuxQn݀7y_f{@ɋoB,WǓѮovW:,T2[8GXmҵyH"-ymGL֯( ܞҨ04唗JoroʟK}{{&.+琖9)V"T-忘yl&[Ե픁 ND#6*O?8I&KKk5-IlU2w0w:,PVڵ"7Ϳx((=lU#_l>].4˹.XrZ|ت.6^E"':K5vI%T-/Mנ͊^hm5 YUG"lEA1Ib͊6*ثb͊6*ثb͊!7[vd`&< G-lu¨S.u[)m%5'.#EUW*Aم@?~+ɦH9Kڶa^|3y>.NdAWprFMf(Mm14jj䝋 D:\LAw##`6K6Kg L"F2hSYᚶmaD]d<}Cm$VIIOl IsvAVYJdcNȍmO8Y\"k#\/2Ô'GW"pMRw=r[smiMOJq eeJD47ⱑEydavv(QcP]+p='yf3^m LdQ#j]&cJ-.AT~$aA74rG Xڧ"eL vB|٨7 inM_ס9c0AUix\2Ȇ#G|Itڔ77r-[YXV032*;gޭxtl>Τ GS:}R(O7`:d;yk^l7 BN;R3jK72ڥV[T@I4)6wPOmq`ZW}N2Q!pI MU >A)ʷr$oDZa@uvd*q Tb::֧&.B[Ps;;h.l^ {Ay,Iqgg6洚FqGolv s#TYij\}}.ⲍ$vFr}ƳzXn]Q͞?  E |^5?>yXȵ8|oK*Zni2i2ݞLqrN`a][,|0^OosA.N&nN,J^_g\\xhJi;@_ɹf]R a ,mAlY{Y'p]6R<1$]݈YH%Ԝgųkȋ] 5IZqv%=,>#wG]ERTAs\16y=o)uᑉeeմP9EcOl{38䈳2Yx! iQ䋔bǩ\Ԋ|zDܪjиRbBV_VGE^GjĈLM[4H ĂGwܖ ӳEohUn# Nkzލ#^N*Xf Ocqݰ*i4]CC==KNeP.K4' E鮣QZm1 vYDvH zs($dWZԵYk:~wlDܹ%#K#W? H:9آ^HDdw;H.ʦ[U#`Q[;O$SF[jeN)|66蹚;7'ӲOs<۬Ѐ}LWvF ZrJؗbP7Zd(J{QD;5;P1"%"Izݱ% )5ڄ"ڒ_P< ݇2)a=W6FS2K;8W'Ť~fNKr2pqh GT D}v_}P˚nƹ;%OJB/$HbrNY>% Ew34ޔu8Jwmhd{^dMƥ-m7P;2R#jAۛ%1i 7utVFB; :pU<K2yl*^k+;xĢ9y+hbej м`v[i!+o>̏Gϭ?] ׼6zkoxC)e40dZWjҾcAOPSf!XxTbȲE[i~\5Xt'X%ە'z-1AMiMmK2?/7U,J\^A/#cZA6*g;,0Yh#Gܕ#x䕹 vM/-AkkY-m?..aKޟ͊~fy765=g`-M/|$Pƴڵ9UucKd"Hm-o-'!7cH=sbDؒՅIo|bC %"k1sJ|ثtr/%SDF?Ǝ]8W͊ثb͊6*ثb͊6*ثbSms0뗚n+}I$\kգ$A^kOl^Y\q.v 7#!uϦm$!fަdQ9cuV  KuX7wوv@|UYQA hUkR8ጷm1 ]M}3@z)%:^<ηQ$UPhMae/9GDvKPdE8c QNNc'-휃CBU9˧Ga_$ |;lqF|2ж=q-^=_O^d@ҵ˵8t;KnMamc bɅFb<֡\@YsA1k0`cT&bH+4`)n,h]% ƤJ$uH&ݐO3-潬8:HBǽhs/[carߢ0Z}d[Ź8jzo\ƈ%d졃4.IOFEE~ nļiw oY+Q0Lr^NLcDga%Jqj "l=3 ;2D[:v3F$vFP:x!%,;oy!RSP$zjKjRhZ˜N@S_o%ڬ\9-'` Z(|3BL$ iQd#91UA*ƒoT9m*XS}2L%C#-&7]z6FŠ$WS⾴vN P-{ݞY.Y.yYUOۨ$gk5 yZta<*PWqOמe"~({Sq26sIpS-. h?rG]rX!)ˀ)a՟Z3o^OѾtΞ91`̲LHe'mCO[e*`MUޫLGqU+ 2<jW-M|zOΥyKYV\I7Ԅ}҆adp!WZCZ82,5'n ?$*Β8%"0M~#h%.t_I0#O:DDD|hy(z"Fv-N.'X _?99| `Wڭ~y1##W@ݫmg(Lrf]vlUثYWf]vlUٱWf]vlUٱWf]vlUٱWf]PZWZ*'z^Yj;N SD:zuTUU͈ݬ֯ct3bCщ*'*vD3iO-4Flv̜M",,gK[qYx;Bb e~y^XuŕԖ XaH0B 2)>VC|d#D)Olc<"r7otm'T%B3C>ݬԷr(ٔA; mo]3wD)O6R?,x<{ZOinLijx Zv^fmQ}1x3Tw"CL#Fy$*#+4Y; s]Wo_ѵSwi*Nv`}C. @ĉriFmWbA7W;f[XrL{e%\΁^i#DULTb/DOԌ #ͺW An$U ,z|ݱݬ.M[ԼbkP)dIc7dn4A۰.yJz1Fe'fNY@j{d(vԥ#l7#Z[!w֗~nnI+e8a! \FPt2:a⁈,G6*DK* {\ɸlo!lc֣u^WGVsa2{\݋ڽܰJ8c =ؑ(1luMcu5SkvLv;7Am8/595y@_KB6155pJ\I X:;ļ@˚Mg5ѿԦ[L?X:SAӦG&Ic B3'o{}2UXL127&S,Q7pGlr;BuhLCxa|cL׽ԥH:T힅->vKxPRX:sy$Np )h,վU6+uETS푪Yv:_3izVA:嘰)XJ\<݌ݠyO]G!N2ia>HHɲ4"`TkBFNBV4YU,wG-݂mo@ȣk pm([.cq˹$n+ด8[iGo5`J(ta㑲R]RMm`C: ixuv 8l݆vm!zSL8 ڏ<4RgkUG?j:= U'ɿMkR,6hdfy92;:ӭ.%aBVxfr{Sk LHMj<0q젶>zsH2-s((Ĕ;9wD;"#o2 ABd1|;IgWrDG[<f4k1$vhƁ}Mka}0I l 22b% @k8EHE({CXK+cGƫ̂][cb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊!OΎu5))FJA!u.̷̵Z{x[6i{*"UmԞjY[w3dP+ЏC!Ohce(5a>B[iwqguջ煃a# K8.DlL!.o^.8NMӒ(.UE@QwL (@|eהt*5CZKmdd0lច`\0BKqwYș&ǩXz{%ܭu4hs,nb\PrcA4?YY$fw~S0lb-ϥ #ei$m:|4;V$C2yGF_l_d@a},^ FTjҘ"hKˆN =ij[|9#@n 3IXS;aumo,GԞ5"*+=G-HphPt]5dV{4BK(H3ϖ51_$-R:#Na<%5Pu*skvH@2Kw>Ƒ[(QYMx*;dg\9@<X0/Q@s<[Ah-(#^*MYϹɌWEtmʞ;RX6r(%"3FH)v]6VEq*5/%bO`L۩j-˚|+^aF%(Dd9W$6Td1jYY[Nmj[Ya ksѣ@+lRO7ex'Yq"v;){;kh"~tGz'2,ya=nZ%YD66ϛR(7}8D;$ZhE<6F0ȫVO. d;ZfN|-yEsѼ˥]MΒ~cHXp*خbp) AJL#(HyI9G&D:tj'*]o'kkif9eqQ^u]uX@ma؞L|˰ :a"Er:gQec#>hji<7w1\p!vc`V;.IuT= nY4/*B2 W`mfEr)QDѐ;fkY?NX2 g`Ykf[c#7-Ȑ!؎=kM[%m~< w4-H7[ $-8Lэn9h lŻWsjӬB <1t7vsjzDwnog`}A MTl^lca$f2(*DXa(Ｓsދ:4&lg$E\h;9a^E <{Qkv9Cb[ɮuk@ۨ$aL\kYIt*ޕ^jԠCOث8տ+kM3ZMj#Rxz@J6*{Ln}J mCE42dj_J)H<]@ܭupd FR OlثVX\Ad{;zLTڧLت~Ml{I^}iż1_Wp?LتsۭgDul.}Bb3IzlJ+#6*][̖vvZ]6lo3]rEYwQt͊ADG/m* W|#ڻR{> {xR2*Vd' )C]~NTO2~q5evʲ6wrpA0ѵ*g,C2Bsʶ)yzq6ͱX@q%F@,2P/c\@RִWݚF6CV6VW&1{R:ON"fhziq$ώT"[q,N*mgB '3DkAiq*R:R$S=NI+$2C 7cmd#~huV@^CvS-6MɿO<.pr\3pt-)qjgn-,uuҞ-уJx#=2$H\>JU!IT|c{m+uQun QzR͏V٬2\LHڙD{@4k"zG۰Qi:EK[p ɳ=z^O0]Xw{3Oqn/WcıHiqOm996'- GV|kr yf zG=O͡p96tդɐ+o1=gW;ZqH'#,wc $Z|e;YUݭiF>VuKXa{D))dhݙu6K+VzT^<;x7Cf'9@v鿶kX`rNa') GW&vv|Kȑ`N;o2v|cZbY6Q8:Q\l`kp;vkY/e, W2pc&(vEM#HQҐdP ]S֕6y"KFP8. 'p6yKXPzg0SɭOX̷Vi4<ݎsCuݺ1D_Y5Dk hېh}ISN[Kj(JNيNԐP-ZӞGs }&GLB93@ X=NO?b5{ٶBo~Y=u&{R#ig v+peKv^@IfZr|U4=&!as;5+"jmn $knVbk)Ր\% =-co_JKE{'lC',ɖR [qpno"7i_ެD$eΥeZ Rf;,'zSզwX71 :]|Ҁ9}DmI)dD豍5';sNZv=n* H"/Pa H~KdQDe#Uޭ'ZNo>ypV0hQۡ̾ yA&9,fЃKȟ~}_Y/m?JяgAR-Cz2b,!J520 ;u&I++tۣ2"?+eT.!xP|2r6!FlW!}$?Zg8HcfvI-cd*{4_"t)jͻ!({Sv+ͭ$$ 7PS%[Z}) ll CM2B6O' .q"'5AkQ%$^TVsצ&<,m\ZeYAɢ!@3,.eP`]T">]*rXNVS'#ۦdT]Ml.ţV .%gI$+H1F[M*;^ؔF@3 ٪mof[9(Db:Ɲane\O+EU e]}ym-6#I#V ;aݴwʠw u NżoqC<,RXdRzniϢrID@;[04(K! ,O@ܜdͱt(Y 4x]%Q~ń:=OSާ4u)lS/l<>oŬUtD^6ahQN36KM˝VQml-zsmF/2jkڍƥxۇ.@PvUPlU+͊"yZ5yAP]0X%C$jȅyFRE6*?-W |'-I.iA11WvQP;R}Gאj:s_Zrwi Q.s lU n1NXM A4lU<瑯5Y5x.]:Lա:NJ(% PRozsJތ (d!RE+X4Tv,wqiޜTױ͊i[=NmA+"~ 7@lUkiڂحZ,]51)ƻtlUiVw~<sgIiV2*WM!XMX]X"]6s7խѐ'KQzUu*Qt'7:S:߈wX2UEmfPqz;IuRyMFlUKV˪ۺ6NwkzF֍2#%;uV.\¶5-wBS"ҨYU94F+8;)Xn6;\$cCg6[N\ʼn΂B4O'RG^Nt' AAe[[^\i[@c]@Dl[E{nIŃ)qd07oZy6 x֋XRP"rjdy1XKvun&ƻf9+N T *+3֘CSVWq@RWcƤ&1³I-J>cIn|*m)H-sYhd~WVц{a:n1wbk;$(Ijե~X1;I k3亃Sp)55@;DQ.#ΰomr(݈W\-q}u,PT~ozfFt^湸fn|/yBԵ \]a(ޠ!P60HBI?Rx߮k$Ӵ00 [jO{ HJ7WqiƠC8h7_9&5t4Dփ5ss%̤kqE;=s.1ev5{.9'Oa&룑V*CB7u F[[vIjL2qDq~*Wd Z KNu{$E-iPN'a)EW[VkP R(ƹ m}>eDenʻK˃hާrtk$REñJ۱ ]_FXGEڃH*ఙ>A|ጂ.˱co)g)jUq"7 u=XL}Q5=Tmzߗ4]eؽD;;~9<[ɚ>"][UE}/Q<s*z =V .Vڼ! 0i/O˄tvz Ois kWnyp7V˥iV8ƿ%Pfa3'+7-%>w޼ֱ9 Ë͊j4V5-|k6dR,rֲ4߻r(JUo&k5֣떓{3wFY/E,YkIͯ¶1GTﭞKw8Rطb}K+hZv7^_V#+/E6g *:ث-m<;Il-Y}/Rhߪljz}9WϺMΫۙuz>('$ x(OlUWQ.hk};]Ե)n ;<fxCN<ثGYGFDwDgH۴B 'avU [% No`.Gt$$H4ϼڗ_{o 11Q53J2#g(6Z- Lb[Ub)82O.<7vΓr&B}E,I mӾsW*;rk6ksRDe G{(ɰH鑍 S57;cBH*>#F{m17+]XZz_YK pG4n B. [LIfT#8BBG^xԎ8ꡖ Ztޘ}iqR+8 #]3/S(4ANʚmtQ1QOMܦbz]n%7 d@TQ㖎{weYhr۷ȮꇾƩa.l^A|.m>-p}A^68{Zf2ޚ!{;^C4%H]H܃jeڨy2ܻ&+_IUOqS8&~HJ%e)edqnZ{23UC>ާ*Gfv]GD&'GT[B427"Eyq]yp33l6>#l_~VkSߙ%S`sp y;nDdn-׸)e sm$D%QK*ԉOWƸz/W`=9XovhP gbOh(x)BޛrO e\O(uu;jMwW7da.9ڀXһ⿓ctHmqm&(h34B?I/$!:~:aJFZ|L{@*x*{0 eVĞ veDMl@G NKEحGxʴrf(A/ zyv+Ts$Q5?4f<ẅ́tgJ{%pTġ75$mLۭ68ARy̓yr˭ jc{6p ّy6kmދjʌҺ_k}̛'[lmnGZN_Hm|&5޵a5"2EKǸ[gwM؍o=WO,=5NdQt P*hXq tƁeGy?n<>_/^ZKbn$. x}M\gӷC#89˹XI=_aާ34@ycL[]B㩌!@I偦GQ y&&f]dFǚbN--kBimix!W^6*{_%^XjoaoMi->iY'fqKL 1S6*Oѩ]iEf}NJO/;s$`J]G.ٱTVkMS4k[gH&pi@1UzP]yV}c˗3iZlnxMp!ZeF\ت<{$1iSM%l(I7pRAJw͊{/8XϧAuMsOOU$)PzfQ_o lj%I-QIW;/TwlUfM^Aqq-Ւ6 3b0~[y{hy̺sDܸYN.7VoZfT&ɴ#al&T2כ/7༨|ث͊6*ثb͊9x!Ռq'F8;97_rA}y< frǡp,*m6_4/KG\FMHدј\*)}(\_3yQkE :ep㘾'01ޙyD)k \4{W:/l%Y"2~Yۛ0=Ԟ6:Qos9<{grM(}'2ݼ(%H*3F+,)Gh7Nm@;Sq=Sb͵Q\9`*O%nY@-BB4(qU $d|"O,Rshܸm3Npr0P}甆"'b,c"e!⑨$3PMd?VLJKKnn@Y'@O&R/Ry&Z6y]C e fkGA-Zff+CһRnH4戉ےimg\Z\DAEp?h{`2zw6 ȡ$LȌ _Bʟ6 -ſ&;)zә\t7v&+.C*7}y4GɔeWךvFSN֛Y;z&Ŭ|DMʔ*([WK!a&ynvp ] +f9 kSdy%ּ޺dPM8I 4cJ!-803K P SƯ[X6֘#Zg:VVQWQ-ԭVpR@\۳\ؐfTNN']=lj v -*#2x =Ԡ`NX(2+PYgZ@K\Ќ@ߛdWtՕߧZe|;lr\kV ]܍oTq:;Լm|"T6G fٯZu$Ml{u.%gdtvDƁ&$aC-Gb8Ӯɧ_6\bG{v7V)I7IGaP9};WNԒ{S#VP/[F({v֚;ty9JP' c\ݜ}[GitA=׍5tS=!byG+FX>%*AEgTTl( $t4?71F@JKr cWΙ1jI +5 \qzxezB*.ET|8R1Ҍ"HsjIF I(BLÉ|問q#Ge|0]S'}]ѭI[y_ ]̗UGZ N~U̷^t`㓔ߛ^c!n$!B*$[ʺuB/K!> rvNssE%#hޫԌF1h݂dťQ[n|fv>i@װIsEZw~y *;RGϧ5ضzwf }ek+;іAZ|2Ihva?PNYY"1F0E۱Ims2UMLc%ar}^xb#SKTJBn2d)|0p$JpmwL]KȜ[\5K,o%חCA9b6aǩRh@;j4#"8E;ٱWfYW巜~wlך]Ɲڡ #]ccq^K]3bƓc^^󆟧#6qXİ< nc&)N9y o&F{tCZ5i;MH)$*v͊45^rOyKt'Dmfi]n"GǻoJoT2y_ڞm,kr!`&f+mO4/˭'VN|'~J7ItFKMvUhb[kPGn])#46*h}~j׷=Ɖ}&5tk3$JM)ε$Lߓ.|ZdK/[rjX.o /aZت_zטLVi'2K,j<7<@3bon˫]CZIu]ٟQ6Q'[Һ0 Rxqx-v3bf]vlUٱWd-MЬmD<(am|DcⲆ;6z[̎]zg{weE x`VCsx)UtUHĵrAll;X$\ l[/ARjLƬK!jaFF֪axe|R.͌[~p0|VDŽi|1xǢ`U,|C>Tڅ-$`d+~y:7x가ƣ&ZuİC%YmһW皞*k؈#Ef<~+E;Oi}a:nH ;xƩ$ 4{n_ThM*X"\28^OEϛIXY5x3vU j\_XB/ >9RH^ 4CftԙYbKo3 cHU翭\lc/͇fϕ|d&~V爛k.VG?ph7ͮ}N~渭 by XonOc?Hi^͚0,Zn4SN}8n=!JxZifk t6m;<* HR)JՏv?I5˟| k``RcjǓvw92۱uզ zka&/mhuf=IܲPvKL.q(5.mmmlH;6t=.֭"E'N:Ǒ!lt>8Y%*(_ՑɖS9;^ZƲLT M*$ud VdOL&+ZtW{\m't9Y;ش!8B=YJ)nsE#6΀\S-ŭy#U ysPdU~,?|z1XVqUb/m`} ]˨nm1^_,bh;d w(GRP0%MwndѹҹleA M?Wr- ԜP MM_946$&v'`(eh5Rzb.݆ T^Tl>*@;"sFh&۽Eԇ͎I \T,}͊}=@%,aEAb4;mѹʱaFG͝n,&_ZߓlH";uo[rq4-ؔqA%ԱJR2ah∬ʗ`t#Y5֠a)NnmZ bn݊6$NGnO5ԗ.hdh̭ZoL]$ĻMq\^ I;'m֬z/v ڄ2.:r#cp[RL$w pضʜX =N*0űٱWf]vlUfV )؂;ت޽\@Y:LI͊5 ,6,`Bh͊]vlUٱWf]vlUٱWf]vlUA2ru?..9IFe(+A?6ģec-(7"B„W۾%.?FV-QE#oPʾ`nR%7zq'"HӯhseH" gC[d%' Ok/HӘdYG濶2 0#.jr4<޾4c8I,ONm`5byThԐ RXxK;( ~^\=%dUu>.@ǀn8XH Em۝Bh-8~(]zdK ,څiOXU4LYkܺj:JoLn݄ ,GSR6=&3N44Y[%7hS/AݶI&:\R$GlǩXaՕs»R2 Wbᓝ8ջ7'zƔ\TЪR;dGy"j.ztg=A.65(IH鈥QXbY$!w?iMXny&Dj_%Y.C^rO(~fn,5] xueca5hNaն'jkC#\=O bT2V2*er췳⑞ޛlvA$m|B2*+(7C,h,Ll_67vZ )ҙ=dħa`(;X*,L(J,$6 R9k {+qSDijՁ KqwvƇ7c>z{o[[7$#"vZ[FzE'(v%mA ްa6߾JSp&IIk+"A.HO7cB,0H;4 e~xaHn\ƨ>+Ma4MN]?P>0zrY|Q,Qv;GD6^s'fRAII4.Ic e1 `.iBPS3e !Ybh7f?O|24HneT"pJV1c.mZƩ+v&#&&.- EJD(;.-^M '"aJ$i4K[X!5)ZFQZw9EʝRnbi7H$zƋlTp`~Jr2LcI!IY\" UnOphJv H)!Z.6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*تdZ4 Uѥ6)##[olUky^[bm޲ 83byG͒ēE4r-̬B-͊@RtӮPu.m b,##(͊7ʷ)jMʬm2e^5 w9U#ByΟr'ORFNqܴJ9TXghZ *KuoMֳG|!xew U5͊ɞp XZUݏg͊ٱWf]T !6iX@Y(sb -# QQU`TsbtF8e;9X.]cr:r8=bRak9}Ks@)ӎlتZs1H1>TlU~k~_ywn>lOqgM[˺07]OadzH ^Q>Lkʁ3bt?zi&=ͼxJM сQd}/~h}Y4O5[E5YDf $^z`8}?͊9>iZ>ou/(eyqT(J~?R4~C\y7׷ZgL.eD RP[_M*lثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊zW5*T00-vD,{|ITw͊s]f>^ඕO5ͥe ySM?(Yv0mD @A*EMbEǘu t/Ǧu-ЙDmH_sbm^2:[vimÈ56*ޭ]gVҬ/ ֺ-Zb&#lU72ǡWRZ7ԣ1fO!x6*mO4`ޜQd^{u5|%B'%()cMbͿ:C|6iiMo6/o;)xTت7K֙65/ۡ1:zlUf}2//]O{ۡ-17"jY\J͊p4 墳|)i K9w׏~͊kZέ$"-f{Xn0)Wj6*,;3{;փ[_^+¯(8<)ǎԦlUbYk$A%卵 xOVI]F}] ت3~dyvUd[Ivڕ0D-g eZvzSN.c\Rg*%+֍B Vg~p[^AlִU` dzlŗ6*+=JJVKy)hJ[W6*6xWSעRn;xu6*hZ΋Y։Xʓۉ #Mף4Q$rE "6̧6*iߜlun+ kI4Civ[L(S6ܞ6*<smm\K6i <3b揘GXCjl-5{{Tm e=eIF+Μ;sb>WOH\F%ꡌ\_M7ڣ6*I.k4O֞eemaԖR]OMGŶO.=|u{M#>u#u͊ ͏ʛk-U򽦡ZP65 GGo)͊V~e<_VZc(㶏ӏ'sbOV$Yא>oo-ދ]DJoZhۂ-':W]vlUٱWf]vlUٱWf]vlUٱWf]vlU?򿙬{}RKUaH&Y&ӕeDdh PsbyvAF}u5y;#\^' 穮lUGSɠT-q?Ȳ"9j"U][{ t$DNxrX$uOJ>ٱTW ֛.2yȄY+,m)PM|3b645g$o1,}ܓ ?ZS^}vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]v!-.RY 'zaݔ'FSЃ [v\Qy2-|N[VOQeRWbcTӈb.N[L<%]ti8$f09D @RwdIѝ~҃ɑHkjhn:I\(-+ņy@[HGy)fpzjP$!DmttY(3P֘Cj}Rk|`x]!TajR[;Ԍ~p,TQG1I&W wG}_EqKx|. $LKque)5ʈêiMo++˨XIN[u+ fH-K! 9(BR4&V5MR}AJ2fIp+&&ExrGSPG9 Am`3hz7VrD%8.ArTu<(H7hۖ_   P{S;SwSԬ$:0^o7b2v((\4-XXm;yTG.KI"M(@Pvk̺K :u#q@ ȪCBvkH69Oech`x$}^Taـx&?o#|ʝ,^#j#lbGp*$)4ڄQpY S^'ez:+Mבr>RݎYՙA^'i_f]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vD5;+0YaT䀍 #lze%VsUhO"yA|2+-DSX)>$hJ݋n;Il~-JxWHvIY#~IO''rԦdG'n,h 9NфpWXǡ=OcID6%:/<~s~miֳY_4;پ~* ޚ3YMEiumJne+!E>t Nɾ=6\y/*zo,̑yNn۵1[/x@@k@/֬/t9[ݸw-=sfF1~Fn >)S8okzG(5];z4v4N$0\]*nva,([KK0Q;eA5Q]F`r)@|}0#dÈ/{qCLEzm;5yqZc!}:`p9|$da2PӛrET+6ȕ֛A ](A#trDɅ|JlߓZ8cո)9g4?Zi#[YCH2bG)cZy8E0kiNb#(Lgi3%,c`//b[!` 8`>!VbZO;bܾ?*G P(׉@D^p^#C!~`m[!0 *Vm O˕He4>#'^SE@q73Y:g X+pTv,ZöPm;](ɒY[gzóg.bY}IU==M:R;:?$|K#U pA,.c9TpT y,V3 .;u`J[K5kMa Ƥm@tD1Kb)djuxc0?ʒIY1v#mrp2=+Uyqzeq]yT!'* m;OyM$%SCF;7;Y'N.a+-ZB@Na&;{q- ; Oi"sK_I˲24#S9k)[7^x[C;PUZ흆n=d=Wmv "ME8e t>ÙŲ4sL t)#Vv5]-N%W*)O!iv$0#"LJ9Djl;ɺ2CTb{ey -՞ކOاVRJ]J($!+<7۱-qP2qPmHvI 7F\ }k$Do2 ]ݏh3r ׎Yx{K#F%WZb:* n(-va̻{J#$L6v^rh|%5WZנ4 "ɦ1Z5(GLej3tړZKbE`{wu/ ffNa@ X>n!v{dQ6hEǡ8f$HNnܴ+W a.\uq 9YPߛ3YZZ[%x<)#Ͳ1AjћnԶEܕlS͸*@:]ݭ5i4a㊔e=FBPi*E.xe@`gʩϣyl9߉'p}l4ZZò+~OyxuUy=n=~ʏ\}Mq. m: x(a4Iss<ː@wuc#n";E R)wvCc}&4$Ȍ~0Avy7Ey]GQgl]∊R6̎˄b?QF0Ifbdjֺ0j -vXrL7I GZ 7C3ӧ[ti^,VygCOI#F:n9#;dIh=MiHu)`OKA\]ZȖJ/"<)O_t뇃|#zvӭIGf6~>̆NWM;"IvJqCbȘ^|O|)2XZܵԥTS/Őf݅ȚpHtٟ. NdKYV("vf,v]m2~rRh;KT#E>yCQMKHǧ$R 6g9*Hh|:1HdGz5'"^*~;sg,'`*Ehmd^ٍqƃD H\ wc^*9K24_ YWE; 5=^A\&\B%Eit;–"7|"m}̦kYZrYnyCb vWâ^\5|e-9;uhd1rIrH;,{4UM)F4 Jk0%Z>E$?|<&rq ua[s7#Iâ=MVnݓ3[ݫ$tЕ.MʯvA-Yb]E=>쳋nn1 Zi%fW nx o|K$euPwws(Ƨ3+&7|ݑ=G*O(ר#Qfp2 misu!6@ QSE'$F `МσoJ8uY+WQ(|bKj'Q|@{e#na%}I+ymLHbe %iiFƲ=)5)Z:W - ~WMtWVV2KG;1]$H"݁[H4?Hp)f#rie$B'@[[k gQf^|Xe*+;>=8$`KViroQZyHZwxa@\GQ1.g3Va>R ^ʅx bNvWg9տz"5_i9-vH!9DnihgiUaC|]ʉweANb[%,/2@̇v}9]P#Fݒ4E,W׭"z3zᑈ7l6vbksy4qڨ\ҿl?Md$c|h^NkP}9,:ڣm;IUD7ž*j3~[-ޣ}ZjJ^[2t]=96iyL%5 CVC0RB߳Sbb9罕][?vhSl()8|1Knf,ŏRjrH:bŬثODyK4Fme^D!!n P{nIrEM:()]K,x)mҹpj*8+y'jh@i<{A" &~r`نRkXyM7$o+7a'Y׉ɑ*gha=n#Hm/dդZ^Kk)"t@yB-OwY/*Xn3^i6.o t}9#%qE  ڤ:<pC+x{@RdeTWaˣ9bz}5z(t%\ޢ*.h,]Mdk |ity-5R}B4㐜vn C45= Jl`_O֐֜oǣLܭC#=O퐏;(ϖX"pq9yV[1X9'?^M|v Q,R\4*(S=owpηTӜt,2Dse7@2:,R{e[]&2%*zl%CJ*~['\^Όʡ]c'c̃ O `_U[ {zGo$©fhH-&jE@]HQhwzW2M ,q9~)l*O5+_n#[ZLu99 7Ѥf H $DJvȓ'bWחVAVb8DA|wH,v\Ԁ|US䄫ޓHg@a>lx]fx2DG&ަEc.]Z[XiWՑ&4˱d36KIXβK,ފ)#Y(1 (l~Yf^ >ı[AF۟|2B #*8FcɈa&Aj"8n>9! ZS7HNÿ_Vcgۜ04ʻ *3їG`Uo#@cڴ߶]-^B*`'GEGܭ;2$^d;Mf{v,;S=?RLDrӓ!.eR%ƥ40>8-o 5ϭR6h뱻B8%?,$M GCZx`1l|=q5b|Msyn(tm*K0[F?rGSfy ܘ°L$4CМBR2Q*}7a; kt!Wdh1ݜ[JbKJN="y=rpk_z'j_$P/<31Ǔ:t )\u<đnUNW<D-ެTN44(HNЄ%j~2VV_UZ#W`kʆ!QJ)`רbᑟ56*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثԱ0fڻW6oW؜8b$$l1iNhEt5NhEFe;[ wyݐ9j_C*}4fR<9%G36POa8Ekskm3 "kӁkj{Ε`q% X;̷V7%1&vr2VYĪR@򓥄np&1|ףV@8ĮI?{e&5Ie4,nOWL"{Ӫ +2i66Ig$juΗushTɺŰPuzҙVs\[W{kaE=Cf<@Jrf;+%fH]]@p~hW $?tka`&a!H)|^\Iu/(r+n:a= ?n<֕|k)j;pۯl ye#GMW^F}xUAg<\̆q;5mk;3=Xi\ SЮT>oMV1L=D6DE~b I$}%{ܫSn lNG9GG4"THGi#O85PA*AZ1Lb>XЃ|i (:O,~ cjQDf|#G|r/THMPAa8EF"&||sꖈΌĐ;u+X]kr n|qst1 hAKy;3i|7Y ~"jֹô|u [l:%\Fs{)sڇ$F &DM(dbV4'fѥrz]{xj1ZKт@eэ]o&蚽 UE>:J^$dn$*<3Z"D*q2,n!F&IV>Y;ӱ PjpYHal-j5#=Y(KIixMcWVd[@K<vBil  3P r1jr='&(]$RD$RT6*O#5PQUѰ[[&Xⵁo8Px&\<$zM-B[[q) "[sr%JcOqO֙"[H5tWP+',VKQn&nb(F<;d.y͢^{HX%wW|DŽlQ+5P%2ŨOGѣ|jscoL [(Fep[X ,ꞔ;Uvd; VKt2Z);Y GbbKgQrH23i^,P,m#*?e5^݂K9j|;"m/5('AR{sIݶ|n FHzUwV{BO'-TfH1k`_#ioy<%O\85f=).vG`O-kpsE d钌IGWb28"7n@`-P7-,V&.*>6O'g2]`i赳I+gKP LAڞ1TM5Y󙍼ꝳM<<^WFil7ierҟ<Rz5ըw,)QI~L/Bp`EĿ2-|9MsuIf=~Osq$I$k@8Hw#cʲi~X؊!Minef:0|3Mg6NS YQ-,lT HN"} ؝@\~x"EHkoogkHLٵc-!XF4 IتEl4*du#UkK`CB$(;3<1*F˹vYeG10v)x.Cbñ+m{n'w5K偤;:kjoF[J\݁-i$@~'lSn+m*k0dJ<v\DRA!ƹ*hmp^s9_T4Z8Ngna<\+d F =3C5{<,hBֆyB *iʟ0G= ԐUWXlO,ɂx #!&9KdUeY7$ߏ@;1LK1iY`i,0!1{d?Oz'4ճ_GP'];u۳uJ;ͧ&>/z/Lotۏ^NECKY]ykUrvAx|uX|a9si֫|,#\"7F)y¶֡Tnd TT0⿱$xے1V)|iu7Crb,˥HnT{o6vAK%e*cLtxt)8LU%(;ǣ-nWվ,Ͽz AܦR̙umgI? kS"^ˈ~\-tMo.PJQk<6Kni JB?F4 ٖbRsib-dJ|JgYOOSU G[uv+aeIvlUM@\[4EW |@#<+ ԯ#cUs;!8Y mM֛W|gkk-i q^Len2i9HP)@pӬE̷H$ʏ6˦qp2吙QR+( X+k~C/Fu{1ި;ChpJxLv!=J4oރ;ߚaG\Es(-qtF[6ɔӖr;[˛luMQUdbzl,yE\M3ihbd{U=ۥ3l[ " %WkOxxP p-^fTB|<:ӏHX8d Didܞ#,UaqMaW,b 0$݄DXUkf4|]?N챑DZo5dgSry*jr \F"6f^f%yHm})y˩H@f? ;.V[VG9A 5x)PXy:gR XPp~€Ԛ/@X<}7e_L%Il MAWO4Q#@@I`з 3ޝ'դX9\'g5!du)c )lȜ}6Î˰kr @=$p%u)uIĬ{f >Ɯ-v)q%؃ w 7`]d741#J3 ~H-۲AW`b;NZsB?LvpOS ַI}5TosL`0F>gvy}l}^`-uM[1pLvF;5*2$I!\L ens6vS(i'x*G%Nō0Qwibfy$--Rzf'%b7җQ.(݆Zv6'<@Bs4C('8Mn $F !ZJ<7')2M35h*;Plj'waO ٔH"3tY2 Ld إwoɭ7Qg`K2[[ 13U;;{dW)?pEuf"4$c@GZ;ɞ54ͬudƺ>JUf?AOј;ڎl2G,ٺqLdsKA*Frqag э*YxRmeZ$s(_#KE!0+bI5Usȩ8CBU3#h(1N]u;+?ZHQR$sb=hjh{{_~}4F%>luW1'OޘZ/8`;;F3;6]KG\<븨ۨtU; ޜhs= {; >hT/H!'0/ˌP0&wjKKmkM~/jv rTW* >'cH_Yܩ4;Lfe lEHLWOhlLnnd>u_j`IR)V,FUN2H'wetp0n@V6G'^^XyQ ()eo(i4K[$$EM L㩡k~nԭf^WW. ,kWuϠ=>f_5Q]d3,JېZL2\h@7nfu?n9w3#mN٧rhVߦO<=?Z]i*eWVM3QӜ20bx۫IR;va0k^+bYMHc^ɲ$0%ӴߵYٕboomgL9B0o<6vQ*M1^PrPQZv3-AKoə;GO$t4?Rgէ6>!#Bi(ZUo| wbƫj\>:`a7*zQ}9)N.xwh2sI"h'`$(@$9dQjmaǯ+ƛr|'bs#LU˼;] TQ{Axs4;cXM)]t#jrjpk oWXTSWhC+-gB?hf@ͷ݀n4k- ف= PS]H#MjA&2mi)r(;@H]z0U=uW[m٧0A5v#;◛rҘs:Fa%Xۮcj@`hvΤ+jQ>b.X[*[ҁȨI'5 //H. "l^H3B*#șUm;ZM,{Ӿ ٧d_^g ]±I.9e95g!';OeRG!0y5\qcTRouX[ˈ z#'0`;XCFcQu31D{BSa3-n-+" ǓE+2ONS%`ASЧaV46 6"2:xNǽ^^#[v-s1=BnB/oD7nըPYWӳ=] [ лI'ZLb1 ,jWj&21۰`SIJMދO  ^*ʛ`Wf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vAov5 w~i k7bnb+}Hr}L;݊,8D\6Wkv]pOpnZuR3@b j0T%Wv #,ɽ1Ȓ8 ,Kɉ4@5(T9Dޞ||Ge,l3A҆  [56M,G*/R=3TÅخ+_KN!;([oy"10+eNh^<@*GJG;d2tlWl&a i+S4t,LZ)@=ZbQbL;nqsn dTf;;޹^Bg#}*ۈ9ERw׵pg.l b nTxdc1ȮhjX1`ޢ5]ż"~SZ9Sv:RG n'ƭ6'۫{^|0X$XkMv-HKʒ|FOsFi[iPˮVwl54haꂲp@w@D YJ33f5'Nf1Emř]ח v!sӱVm%ӵڬIшZsdeٵm-M$w'lktT (& (w3AlDŰ np+[G8xZ1Y4f]7W6,.d(VFW:Mv CznJ4LU(ps_\1oݔ|ItgEK=ޒr䚯/ ǔ cᇙ\)Nr5KzzM%1Ptc6عFA^BoRRjyYJJm?C,{hxUgVFxLTG%/oGMq+)P#9] G ZCeGV1uPI MFQ/賆T*XIɃnKMbcS๛wxdct TVClܣStF@[-۩9N 5"n8lZzccQ@2G}+G}oS_QGb1} sRPsNn+.e*OQy[PELJ(HfqvCuF;Rĩ$]K@OUJ.|]KDGZqΩHr99-V}HGCU#RE\#zKI "OǏb|rx:[7C'-@v:Wӡ`_XG>v:!BB7E 914~!F;4};zޚth^IK@(j̼pHoj8/OM&@KD =\"X@BH=&s'd~ ~Bj6YG`h\]S$7Z\]y{˩8['u*?u=1!D$IW@Ô@ң?>Q;HRRbC˚bv2&BKi/%{h(Y(΄o, =Km[FԤy5bSVzL)c aՙX2LO!ӕ"zP 噜lIqӼltr o2!H9T]ڋ닰<=KW*R Ybثb͊6*ثb͊6*ثb͊6*ثb͊6*ثbR[dI@a@$.mL?%РMwʌ3v>K=N0't;#W[[G\GEs_"#lIvIEg3QXb2cbdXOG@p!Qv8=gX.E9I_.SHbA2§s{Vp^S*hv \CFjVU.-dE(pZ2ڒk0I29#5UtFn=k+K_rCpjЃF1~iG Uk3}9,ݹDz{U,DzVMlX/`)Fmw(;~'}"v?Fc`9,SBOʻDr]fCW9Ny Iic?#{ؕheO!A# Ca+./Oў{ϫ-ӱ fCx*\dBĢ'a_ ّu1kw*X){xa;-݉^^!H rXA#[6GrAȪ2db%l2(uv ZvC<3mg #ڌ@34puj=r+5߷"ސ╏\ֵ ':McjֲrD;{W9PnD͂E}Vmgɴ{§'`;fN|fg%Gt%w$ѹ汹 \(w4_u-i]ǶJ $&⢅g{n\v_SG7eFG`x-Ī7DN_y!dq'(dvXԋwlg|4Z]T1.5~[F-7+洸_Z,6te@(#jj:kv]25'/ 4_DGM_宺72܀%Kt>S'_h;OMB\\eZI Qun'f3Ȋ[%[k[}+xY(ORvm;Irt@⊄3%T ccAc#)SE0MouxDIr='8;՜dnd"4J漗Miv\/*D!5»/fR$oauݤr'ħݬyB4v" -r'S+mBՊk"ȄnǦ#=U{<2sIRיu {0[zrEDugղ|!-Qac B?ͦ/Z?Cd%;$RLS zɀk[\AX}\c+Io8`YdQ`%w'ș6D|CIVbkczQN.8򈞭2섚dIȼ*?d#Y5.R+0W;CD:Ђ5ŤiNI2QL5(b[kJ9_0˓+@Ljv)s<7BCȰ4hZEG%yV"-$UwY,$o;j d>MzζyXvB4P?,Dz(F=!feY(Nd ;/f/]PY`#Mrr~4 ͍M}~TVv>LY3V;vuHHNG_͋j=F[}pV"M>[ I3J\H\`4铭rX-q usGNXi:zD .D4++aB6 <׿0<Ȑ\[yn0OV&ʄ=Ycԯ֘i~d^4X+yn#TG;T4b+C +ZV%0ZN.#W Tyn#XX#[MYOzwR,\42\hldvkleJv?@<0t_9y,j@#QYADF[ L'o SPG$6?dTBR0TF9mMKpmսqI*y!SlU]}i/B8 "LS/M]`c*];>v/+TW`2c)Sb\2x\?9;=wA@@yP5|2XrDnnnHn0qY5*F_#]Zv_'\;pjAN>$SL=VPJҴL2`i\W"˻4vت|2-zeݻӛNH!vf5Ol#[d4 k*WL<=3^ cDjCĎJ5̸x)YDOY(lA>#&^^߷CG, taMJDhEH*GhNA 2$P4ƝVuBoRL̜!]uoyipdZP2Ld;pө1ZO]_OHהSƹ@NlejEJzc"Ǜ-ð."ZVoS!`.[:EF&I"a4 { <)vɈb0ksir4 ߮]:A;^Gւ,όvkX?k\pm=RN |:؋t'P!/9{ӵr&雱EoȈ b-22%(ztPJV01ZI,*Nvpl=͂@,*DEe8>.FtUA#s /o EN9( ΦRKCKk_lkvjy嶞B>*Fic#ІGv8e ZY=.G#nZ\K;*-'㥲]ĨZFWLHSx䨆.{HQpȖAض6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثj qV;twb6cOFgVpFwjiԈ5Vk؞Ow3F` '%0zDxvyI-mdP=7A\1v"wqxd:ZNlzp7-G_}Yڵ7Zg)zd'[qG~c;rcSV";hIcQƞ٭1޷9/Dm:>מ'= T6r5df4۞2H"·Zd8\iU`ė.*Lg|x>63q5SISՖP0+ʞ=1(Z]lGDw9BD>)qxr6cv!܋8ѐ=@#Fy?LPr9Ic%|QI4c Ĝ_C+H﴾&9 fB(iҟ<7!ĂK HV^#M˪K>@!O.E`jsݑot +~sZz6 5ąu*mmt=l-DD"W;@'T=>X.mbihgu@Ʃ.=DTb +(j:mSL"i`XtExÞPᒎS4H .PAvlU׮/G\WXp3'GLO'gҠ[=sRcE"F/;KqXP;jPR~UK4}]!1EG->ѷ;F+Rp5Snfʈv mGOTӰ%VDŽ 6;Zk)u9H#;FkT>@;"޷UnE'lh<5Nf<<yH%@j@'cj|(i&A#\U tZfGfݬ:dʙbإٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]MǪkEoիAbb-.K֫Iǩ'ܠOz+1b٩-E!ٵ "YE*YH\c4gךmHNg7[GEoj8;ӵoื @JƢJ+dIS|"F,ف.֔t-/Ff NOs?Em%:^!?qYC}J)$"SZq:4Mz߯sKPE$8`Fw7 ƖbĬ zQ@3ΓǕt4x|Mz5k2RFĪ6$u23974k1xvRLc#dMLlX"Edod`1ohmr4*f$?ӡaDn inj̼dIPg(31OM*j$Ŭ#DBNh-vvlӶCngZܞm+MҵN+K wS6, Kp9ADe(ҕŝԶ(cKM״֮2R Sݑ e$A+Kwl$s͊D|bKv_o*9s㌹l"OG&idF:پHaecYuvWwws#[1PZn헀FDr\Z0jvZ+/9 V͎.՜g;|.6фHzP)l2f4v Չ$'E[(~z  ;50yT#^H#fj#1N܌Xz^G|ȚlyjwYP@K$DsDa8l*:ԳK{9%@xLlO#ne=Hb!e#<[!BGsE%t紲^2JP8rrHPeiuuw.&!cEOt_˻}>MM[ӡ/u+ZZT"peSԎ1|][SˆԾR"wmbEa%g#/$iS HW)ipK2Aҧ|b9v唀~'rRvh9ZFJ(ߛ}gG=ΆaL2K7<.H[[:icQPmVx5s)Q5wWl=9`KO nvYc gO.)iQY!ԞNvJ*hG0>9nbq:|RJY}ҝirbvp:7Ƣ#/{;9i1c8C)guk,rE4*cbWL~[zͰ;}hg?K/TԵzU:MRe]d>aI,l91jk!Y]b^nP>NۤWMnb'9PE~oGҡ(ٱWa=gZRcLW ۓ TvƘ.kQ|b"cJ Xx`AٗiZl{oi4VPcJWf ay,tS"^=0oZ{Ϥ(D&'ck4R*!2q8Ia}j"b(N1U5hͯQZ>hg`KدZKGXʡ"5>3.m_-8Y髦J;H= tds1RZHQFKW%Ж #Gc1dN)4g?ʹˋ̖ #a]mOR5Gr}Kswgoӟs_i*44l$\IcB{e{L_:nsI DE O%֙-3v$F)E֠ǘϧ}+wgZŹ\73QϨg1ȋ1Y uQo͌;RnJӯ9M%[N:ÑD%;JN-B(@dմ%Dz. ޴9WV&TaD|H<:W ݋W\)MuEMb:Zc U~J+A$;":Ǖui5􋟨5ɤEU)}><<T@:v~+:߬`+ڙfx8y6MMiOl)jQN43U )-a1?c@=ώbIez̠o|JvF /,Y iw"F?Eypl tϧC݅pf7Jfnn1490FT|Dx{du{Kuk% HkN r˭Vf+jK#ЂGK Iv 1o\Z].][$Hj2`[HBb Yg2/gm$KM*_P[֥>YTK,@دXqdr?!GPA?4y)feIvlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWd?Y'nlߘQd$Po3c~F J۩;`-p(?nòZpxd$<=M;#mZHIK^xe1N+J&>jm 2܆P:ֹ'ֵؼ7b [re@#˒ס[xo%Z};i21̬U{muu%kICRöFxLF}b>fѴ3jt+o24^FGad32e!Jԯj2v.]'Za: l^eGq^-ݣ8@ %Z?4CG)ms2#rLw4# t{Ki,іY{և*Ϧ3Rd#gaz}vrSMau!PdZ-:q\ݐ>]h2(xTx[KvPB3I";>cU*)@Bx,bA*ܜGdNdԵ=CSPn5iXs˨J5yX>s%T ]q o#Hw}vd20d7gj{䫯 k^ca{r+]hDSN5B&E_QNWf&z$lһn0v779u |Gі4rkkZn-yJ*jrxJ;^ȱN&9@Ỉ;_4 ـH4 Q+2snaͬKsbOF2%5hLxljFdrDqēK"FPN¤iTb{;x\ȯ%W tn8vWl./$ff# {Y n1h` ijx3T=WNŬ#2kaҤY!cć;qQrnHf'[۲!וw<2G.5Ḏ߈+'$Id>iT ,CXE=ڪE;x[kQM37E8'NGv :GM+̬|V2<˯RvA#ndmٙ6MNO?)=xpsh"#z)ga1=Ib(+ׯLW\R[iDRկxE&i:e@<%H+ fWA_o+_YMw\ v#5]#r2R+UYQPZRwlтynCXk1JqNĻ sucqnv$ԈDLJ7 Q8Qݕ7 hoCV+v'>8#+h~q-S&"v-؊bMn4_U',GTq'KRV.+KnY>-dr:|0Zfq[JQdlVT6db Vw-9}_s9uL07a妰ukoo(vl9}R`]MVf+ 8%zrK;*#PEK"t@Ͱvz;0[+FTOO$D@v״ mLGԏ24ڣvg5A!%fB&;BH~(TTĽ]VNn,0{s.qEZyCp"ך >̱΋NqWDٰEկChq7fZf!7윿&zU˚۾v+&A/Λ9LȖcfa*~Ɲ@ÄYYc4˖}-/ÔTXB!)wr` V9R7vGI]: nOGdkYǗk+ \գP+ty5"hen"N`yKwR.z/ Gr9YpP,Iw]5!LNB([Uts ºg¥ܻN\tnksq -b#: cn8AS)KbEBs!a*sl!uA"ڹz^NԘ䉽xxށ"f_F|wr?"JS@8 7Vw7 SJ^p-L4Y;I<'1Cat;"~\ySQע;f."@FCdx=8#$bއȳSH)@FCeլ1ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثbo4kiɦic4CCdgŰȎ8qhm&wX+2Sx䙭PrIB߶dqY/hhYU#8lrWzm E0Pv`h@e޷ oϨpS}cLr )PhsuM?!* uxÀ {uS^WW̐]B5bjZO̍Vs"w ##{/q@$wo;;.HxJR~&kΚ +ȏ3?O9T od/YT(niO֛jZ}[{[,[5>')Kc"iȓa^7P2,Y.*wǴ<Ī]׭2C1ŢK"W3 9ψf[Alw ' eD02ݳJk[4Iae1:gѬm&Xu+twbCtB@ H,v RBBzrZ+{n\p2k:7) wcJfKXKvq]}.4ZWyn,1Q;M7 b庢hP/MZ{6ԕH3\@\۶NfF!bxxDSZJDiEܪlטD%ۋqZN R۫Y6ewown3--^9"waN[jۨ@Jњ#zYK[7+GXMd<[u{aEEYq呍lEG al4iltCN0f;XI$(&dEJX>6% yYyn͊"ZN#R6'3Aƕh?(ϧ$`UgcYn8Q>ujEݬ-F[]H$ѕU9Jd]mFTm@q kMu-픂бhI ',;vZV[R9T!BD;Y~Gk-\:cWa2ff5bX\tJj0_##{1JxU1v鍲v!f^+#ALܪK m`1I;̩{Qĩ5A-#VZv ֣RR_aS" @bAGGdSR򇔤2ٔyIT 6͌;C0[_aݞ[mVB->]7~Lsna)s|$1SCLc29 ]ȓfPa*hH Fn"Lc*մ h_|G{E;]+к}fTWr2NɢhyjŁ{e dG{ C6ڙ3..HeFŘ<\mnȦ/.ĆFhTRԈ̎R/Ω1O@U;]e`ޮğaC8#˄4C#*Oc5kRրPt͞AO,g#@* _~-7>M(*=φK05rc#)d nڥ>*nN͌qଓTEqe`vӌH+F.&`ޝ}ƺt4茖X#{Uuەv?670B82e[oYH+ƪ}d~!^=:8\0b)m_#W9sSߔ6ԓ12kr>g>nLdۓW|4}N<˻ggCi,e"A&|2*-`絉~R~yH,;1⯰#%v۴1xKrNG従k%͏fv?jɇq|r%v40妟+)#Q%s?Fm|/JfXt3Wv~kEtd"ޘi :R}v$FJNK]5=9Ӟ{taS4Bnȸo-eXcJ|˴2MyWRKq`ZؘdDPXQ!(ۯ,qM`=MIt6C vk_D<5$a ݈zhʡDolah܍@Zb6ڰڃ+,']vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUY40%Ts/& mؔMs񡯅1Hdqa9ؖw.g! ~W) ˓j*Xsihh y)CTSl@wc(\Ab:KcysQyhѷlyO )NVbI-l% pH=rY Y#'vZKb%D|f7XʎPsXQrA;O)4WHN aS[pD^M.ȟG%nd_LF'8f!25㽅Iྀ*VSث u,sX]n>asdydwȵo=ka Ih&((+^1j%62LӦ+'KE,I7/-.Pb,!D|BBx70CͧWr[k@9҄TSΕg4;а$&nڃVK¹(` ԇ%% 5?xlp7ͱNZEpli#9^˰FR4 -im-:VxGM}9Ve%t:QhLO &%2Ë)SM qyg ::oR/xkwp=!O (]b`FNa;hmY#)쑎Y;6*yQ[ [͖ ŵqvs&6'B%V>)>v.ki+JiwVЩ=~絹c)mHԺ[iUt9-$v%wsqsF<=wE5a"է?LaN@xa@Nʡy̞k@v*d r~YvvFgXeM:xΣ#&IGٳþJԈq$mOv< *$V=aY1Qt-.J_5>I#j-~&Z=3$CV; xhU|azn%y-W~K;od(䌧ExIBƂ{Jʚpng 8b=rx2+7s@i&O-݁d&xYh]|<u>b?Q" :L,~!u^BݜP伷mKG$O4h}wh9OE)t8a~dǩ̿[0j1JH:)]OeqN:::4nnD':Fi%n9vxM]x]!pQGN J[-q$.hJc"_ LN5EecH9D1*.ev&;yw;S:``w6A), /oP4grg,I亲K@%h~yhh;4U=E;yQѴ &`x1GTJ@d;?zmVW60L>>6Ɏ&C~38Pq=4M5Mg]mO_sy9SvVf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vFϩZXI]J+T,iS#<"82\hXav5jPSj8hZ(VHz+3QWzu` v3PWpBF1d-уe5V*W9ejGc&f`[g rMMrQg}K>'64̑/Q,s[ ]$q^'ëZ wmvޜ'Qr;om`hp}EWә೎6,ׅHIߕ;dY[7BH\І#|fhqg;rDx‹)SCu#\Եm[K7b'!=V X" 15ZXДWdǛ ~ׂW;Ё߈0ǘlK<ҹ&[m/&41ڣj6j6 4=%Qdy; ]\qer> 6&7XQɾ:UV@X9>9zF4R3,֌*j0F;!q򅎭J#GHd;Pt`&jAcI_蚊_ؕeu*„2WhcӡcAp4G <|=aCmjɘ[jW:=<`*3fw5I(PxGjv:sEerSP1:zS企s=jOi̐%K'(VΫ1 &Re*[#{N{AD4sێƽ3a2nR;VRf"YS⎿q1rHcZo0w1].on;G+rAo^8ec!$cDc%N3h"CZ֙ SC]vFfx-R G$s4𤌫64z vzݝy[ܖ'+/lÜOۓcy.O!AJ{mB ʭ)QA^e%*[KPPWolKn>rY@5A%NȾ]?Oqw9.[1lX@˒NaBAfN[WnYd;:БNӾF-LVTЊtOdCP !y5gckkaW|N|IʣNɜ_$HbzĚL(?<2;5[/-`H2+dဍqv'Xke֕Fjw V .8j KbڱVu35#~m=Q?QG|Փ|eC>͜hOSL;NuI:?--׏M6<$yy_śMq;(wYZՏoͮ}k"JʌW{bb))4>d'pPplNN-F-YgP9ma^DvK} jK| xfgvIQKq+HPK"4&:0i&gn$y&J"~dt9:J )6^# 9Ǖodѵ{d}sD%zK hОe{Jv,Zoue|*ɐܷb@ۓ-JTyV9o/w^,c֡4ao9.~$ # 6x*;-۬xzs@D>T}qNE Ғvȕ.5 tu{k"Xn 1A[]'the`xΘvr@ sj;HmyxTUZUlrȰU1"dZHblvڴHtv!cr=czx}@Eة{sd91~#ȻF -ŤJ~lDZ=m~_edI"G|Z 6DboQ"ZIY=)yMHr:=Fvs&j2i7}ԂG{"` ]C#L4D Z^;wܜZX-hzŠõ<7M0L[]7A% I|~3#dUA!vLk5A(u2~ (obIԞF t8Z֖c*FڹTn1{5h`2H2zyPCQoqH 71Up~skKnfJf&> 2Z{;٧iezF(ESe\_&Ya ~-=0ecEh܂La+sA٬.x4b5Dq'$hg`-fW%ldKwKxƔlŜ3\AVakv):\nB -9MK1#Po+@rݿYyUPԛвSS>W提->ͭV[gTy{{R:rxx*1J~! KXjzdNLj{XxDD}LNARuζ+TA~9~+.A[}nW-rQ|Fduv EG\SXv+e}z!DkqHV_qDĖ sƌ+s<ɐ1CbTЬgÑLp.z^'M y\.}EOE$o#!w`];]k[Wv*L$Ǫĸ4'ῧX.x4ƺ-TճU]{48@; kVд0ʲ rŵt\s U&(Ќ/_yyj4IxԽ~jh᣷<(sY5DIUWU(!G١bsmy@K 2#;M#rڙYQHC3m0%YayH⏋2)4ㆶ2f4'8%WLRQ6;: [3+P,v'7ݟqxѓ!6/eԮ%mo]]DHaFt=ʻSF180+H&2[\ ʾJۆܚB}Mrv2Ghd >ZL] sZ4. Kas^$*:R+T?k2&—T Urii@SW?T.dA^9ŤKg)h ίOPq}E3'uhhz)]6%,j;OAidh0`++KۂBBJXx/^#":H)B;(o O)9^R汵Ӑa!%HG ukn8Դ44cRO5ʤiEX/]Na4OR:HX fA.~ \ V{Dq-i Q+Jn>d8m&݆ZW}2dt zdp@Ȱ~]"{=b=$o3-ΓjbL'ȸM)]l']ԋKľKO-;fd[x$y;&gdvVKH 6r9Js2=[5f^P&=cGg`k;)gn%$98I^]4-t.#FʬvO>oz eӰ(dثb͊6*ثb͊6*ثb͊6*ثb͊6*ثbiy4%6_8k0q۝p qt-RrUb5ISzPT 0۸oYvKf~6/ضk֩s+*EGp6֣TX̎KW^<0Ӵ}>>"yn9+c)[D֘p&hR{eB` hTq#Fp&3d;̞dOIc2+dחA({>_taNqkW~*u-m5xm-&yR5 Qk;"2fH.iƼ  |=VRmy|!ͤ42J3ko }[Gk a8w;;ĪmJm϶QvYoŽi$?bV1nv4{?Cc⾎LF0^"φz5>qS:F={bI}2=,uԦZ# chyM%H8Z6"Pp&dvv-e!a|4/5BKOh- Y6ð7ggsy t/0iڽ6ר^т>t"cw ̞Qu.)m\5i^[o1#nH-B)qŪ{f8K^(4uv%ȜB#dSM,$bƥz[xv X!ʞD5?.e%Tr=Zmv;O|y*Y/MBKF5P'hv@X7#es1s=q<5) шq=e7H >w;xa~plnD@:W,m$ae䚴q`Jeد2Ȗ+iՔuԖs<>Ƃ2Nn(FH/[H~"%eOzjzE3h&L&.7\jWigC@xOescB -[H Pob-ҨTRї Fي$3O$̬8Usk#Zbj=8Z)D%J;y_)[@@]: ' ZvtE|0W;3vq\19R~Us,nBT0juA`j`76ܧɰKH,yXrGn2{6ct|yLTo9 m20Sm0A&ib*í(r8[sh.AuSʼn܁\*vikBYIIeW0]kvK+7 4.ҎKfEc{eaً_TUk*Ȼ W0T-K uL%ur/V (%C+ażqq)C;>0A U+Ne[C4 WE\ >nb5ntEF]]VVeW" nݜv8W4GN^OSظ+͹rא^DFi<Mupq3Uy92Jwܚ{VS^b4Ky Cӫf xD2mWm{}K[O&W4]&SIuHOndXvxE%(\݁. ؎Jh6~؊N*8ƧE6{Gn_'?A.J6vA/ +' 览ٱTs "@nʚqm|s$Opv5<"۷[E'&|A.ĮsX "dh K@%GpH!3i?eKtH^'ICD;X%/]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUGӷ>=~+ tuB9QUM)W%."xe+lJXKz.u 4H*Hni.6Q0251w4N&"Kx)6Pq>Im%l* ,6E\͘ȗmZeBq ~ c}ucrRT:Gq_˭ncs`Z@yOlɡ#vZݙ\Ltuo%SnTnwd>^֣OCꤷ Uc l0B{y{ Zlī;Q A -&7*&e5m#vٝ3Wi8KdzZ<$`u#':.PqTC{ooy:ֳ~["Z嚮q՞(+;8ӷӒ?HJ(]h97md\i$]HxPDIpj4"+I7Gt/SI!V 9ц_6zRY]'(Wa!fU"a$n2/ b PAq\rn_GWӑ"v,FؑJ7&fb52Aٖ?`6>a hZI5 bqR8bhZvL`oҹ3RX0(RYe[[ƷI+f-ӳI?@.޼ _Fu1snM~lSI$9#'pxHlv~hFK`zZn-+ X`)tҴNNK5 }쓡Qbk)ΓIK+,¿d|.KWdwP\ЃUl1Av;&A-~1܍؄3_=Guxem'Pyd O S3-i z op'Nn䷹UgFGȻ8:mN ݭl"iLLbh\dy@zyjZ}Z"`ȧhlBwhjv{>$j3m`9/lt=GT2cͬ4^.Z=+a;)>(-&E `wӛQ"5kpSԃ^ȏJyv7[V Io Q7fe, rp>Y#4V7h9=e:\?P1$i$lz1$=/jf>2m=h-O"NG55F 6ωkOl\TQzR"X#ndϩW?`d`dХP땠jּq}&Qq[SafDu9 (pDèN .,ck:I%qNKR$f-fY2yU\dl2?.]gĤAH$㿘}=֣wto醆6 >φlpDGaVB29cu?5ٍżeZGJ֊F3c#6v!rckn=֚ Co<&V%~?^7.fˑUjY&^4PncĊ$kNF>xB/f4?,!qiY!p1|qْݦckvغ7VoNS)aa_Oy'_>Ï|0r0v$WmwW| , i']*$g聻Hfa 1V{|F @J#9lHR*-z v[WJ$Khd>nO&[J#-ԁW݄s:\!+ 8P;,' Od ! zQrk2'򞷡^iIgJ/9-f<F'q |r{:{X逞ѓsEDGm+%w2ʊN\ր݁u\"jO۰YfEGPu`0݁}..5&^0Hz]Q}(uAyY/9Yhn(`{0Ȼ&添=Xޚĵ{YHYY"'Av@|\smg$W3'7Q[FSvF4k5Hf]]<@jEn=,u _3^iEzzVқV(ݽV*Gܒ8CbbZm%v瑫ž)A4(UEu;˽: 3q T9n<|TdY#R=+d-c*vAY(/op$hsL"T=AȓKnO:|h_Rd+FfoQMIdwD]Х#Ya#359DcC\E,xPH>ӓm濜p\ECq!`@Ϳc5eE|O6f|jzL4:-$}iX5>yPDw S("L"83i~ZU4 "\[\Osq%df/$ՙI8do⳷oS{Բ%bu1\j_ᘇ2D<՟W/#=I`0-'2L>17e-Žc-ࡾ0HMc4b-;PIV%}E6\qau +v߰Ƞk[uK5<rpݑ<_ﵽ9pi3aMw11!,lXT Nl}s̼1Fe c{?B~Ҹ=r@쑎+dث%ZYEj/D\OVo@%;Fj֦ jvwjfvd#X;˺2HHdPGFN""23ե"}oZlTI 1d eeJh!.+], ;"_P֭'KHPCU~n~HF2;{ ' `IB1S{_,iͦsF/T4 ͭQ[%Y;oܴ+O-RIe'(H|/İɫqC# 4ʧ]̯^Qd%ƨ_.7;A9 ;oK f4EL9Y.[,h,Ć,5/1\ivnRhAl#%-vyڵ6ͬ pMYzjSD^>eIHaaxR si <=/eWpjU;g+,i+Y=9R1. ݲ<[,;|$fS\[XIضeI `Hl_}JqVIxS˘ ékHT-va-nn$&)=pG!&%m$E Q2DAӮG$FޒBdl-o:{c>!_ݓp2 HTHw4({`D4RJBsdu2EŠ9I$SgKnc7@#J)S28QšnNDQH46$9ZyuXb!lvL݁ TrT8EuAv˥]HRW-S a.E浑+Yv|s#[g m؝[Э[:)9+,vH 4Nzx4sl5D(䴴ufp* lk*$>x$SK;}n'f>y|qF)ofp4]،YdvkK^"vdXxb7ݙټ4z(höqX:Icb%qwlal dw͂TGlffFQ!&<[;"z ^.VU7N.הGe{$9sRK>TvTz<1j&{l1`mZiY&vlݯFeA)+a͔T .F[rnŪP|;ZrHUHV[eBq0 H?iHOZz$J! zZ8kzBZ%F@(XYTjzFqs> H!'I'燶7uxeV.r%i|N3wR :Rq%Nʛ}x#tёn.Fl[a_*v 6``W[bd)#n`Y5'}=vq$VU' )^l'`>[鼏介=B8WSVY6WfƳ >?Ng`aWvZ{+nl[[yv+V()s:_];q 2(Ս7P6v,m=웷bw1k, @wFRZvQ88vJztN @SJr6dCJբXHEi}d=6FY76f*qh\׉$4c;Zɨ a~uk/Syw#e4FH1 ؇bs $>ȩkXDɩddBvlnu9< Ùrn[k{{~_3ֽvSb@iB6tUh:>e}y_ɟ6ժ*WNhG\=MFX7-|86Xv&mxG*$a}#U$O#tSdmW6@n{\ qM>%]66eb_eǺ8ؽXLA'靨kɱA7dT 8A!~H1 =#f4{Yg1!T}\Tu$,H; ~ `ӾTgR6vrm-o9`gq0OFQMc/QqWOFXjĮ2Z(NN%9`n^W;Q2ltnh?FkJ7bwvvW 4!UGfאe2Y;6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثPJߺ$pBwʙ6+$vڣ<`r] mvwqFHHۛFIZԎOmvhD?74b)"3UvEsgose.Y;Ыٕ쬰Vs`3o!:a>]ژA"ʄ|QsX2]ȮmӬ&l!c_4Ze-}Y Gd}JVK|>eضCnkA'RTc<&|r97b#rl%4cA@w?F)a-RHZ7ySnG3tCpKT뒁\E y׈h&fΠG&nPHۉɇ|Z]N)Opç|v\d)HZpWDIk)N Tqm@I?TfMt=՜*+UljfԮ -\N[a#yH?ɭ0l{uj q̀@j'FZ" yo/leh@۽}> Nf= )~|b{gkwPHo`3sDxJB7e," NhbkIl\¯)MO{d&d"p8Q"SY0ӌF ZS6F@q[[-R\)sE%x c-\"]-kc7)clxRs@d8H~eIH58HU￰:;sNįC%"|vԻ~^(AviH ᓜaٜ9R]$4=)@Z$]fx\w{dH"!8P"_v2Օ&4FasZF({e|6VQ'}ZtU9a6h$ȕιko>n%eJfiKH/gdO,݉A )QlZ(a(RI%׷IH@D",4뇴Vcdn cAM8y4%y=.SSN2vo5;7ĐH·-[ݐŷB3G(,7FZ7]0jC"bMZ1ˏ%H! =VI4J ZHea#h9]n/WM Hdn< cj]7兕^jk$m8f,̶&rz w\Gʒ\o݀xLl,P_+'bshlr$1{4Ddb:yJh+<;O ;ZP&vXT(n*Hid@wv-mq*\zB?l݆d4@Ű%ٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]mc׺d㕍E$pҹ QA**эC?ZצykǦ*gu3ĢNÜR#~[^m mCF<A6 cOoBlݘ2V|ykpK.G(J&'%U'P-TU?wL5y橽!\{{JlVXs J1^]pO0Miba$Wn Z<\[ wuKm%" Uj}n-RK;ghBLjrJ{X}^Lȿ2}XҎ1J{c0q" vA?kSODhbڃvmq+\1Q.%ܖvzRHj;yfr9,uh6 X$J;u51rߓ!L Veo$|5[M/R5ars &Lj 4Ny~U0y-Ogk;C^+͑`-8)FP=^_>TҠ[?`[g$(0H]^hZ^XRFAQG|Ԝ`29iyqi7n^M@`A 0M8a۴(USҧ9m,5j%ŏ}6$2*U@F~V"լ*.y FEW5 ߫#.nTG0WO-N4P7' m2aՒ7y.,8FWnKEJ2Ӯm%+4\]XM ++ԯb^Pt;_<ɢTyhER>0gs_*^Ennݷ3Qc\r⍩BG b%J]Ypkd,.#/J'-C'v!{[4zૹ&Z5(wqk,:gwdqwP% znMT!"&$24iN8q$SZFZE[2mrST/5ƷբZe{B5dzԊ}}lUUskĂz}(Ɂܻ o+,#lY7cK؄I n7釈o\`;qԟO5v?4Ȧf&YSxG'`I5y!TЎ,7a엓M*ǁfrm#nm5AEAie. tkm2خRg-/6,yeq˪fʡ !Ӥ`PRQ<)dcZε{q~58[0今%̳lmgx.-ʅ+I:hګVh[5Xx`"@vFa@۩bs&3<6!Y-Ǭ=@kO_txE:^ZbvSS)\{T'C(`[S|-+Ǭhᠴr>r03Jg4pk#RA#녷qt:/Skn HOm1<qmɒE1:*Ǧ4DIrBnnu)͘{xbgEh;]DEmQ篫Q$,Os]_@ѝ@%j+.SZ푀ma$ k?Z>{*Z?V]Hi=,o,mTW$>[5,oJa=}LiC1ңq,l|ãDdW)< BVOQVQ2)-Y۫VonJ1E\e͈v,,S!Iv_.JEK26IlwHzofJ3"</Ju5q;UGUwR+\|=7k82Kk7D@RiUΠ~ @ƩZ#TZ0!lwANzq$m Xx4GWC@^%¾bLH39}9: Ug+#G]9mCҪ)"7Vl_h9e0!07M4HducM#N_"ʈll۳\`n%.XO-݊Q*F58mkZ4')!أ*^'bGv-fPJG$;.͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*썳\Y+F$` 7LŁU@#8/n.^Iazl;S'$j띷j  WOu7(콁b-#:4'O CEG߮F]H8FhmaV,)l*83.$Su{Xluf$ˆҊ{<Ċ'f""l[+NKyzMVMfWpv֛cRZNt">s~^\\՞%R23YȆ.3Jc˟NWjӚ-hdBLrr- *UH@]SG#4 K9- !w#ɗGeOZb{R.s˩4=^YyBu%/}xݷN`fs|'EzR/4f 3Ίb~<<Kk!:!.'5aȵ]V{g[H3D?ԃO"}JGXC%߭r$C ݕ<%OrO <}vYִ&R6^sB[98w捰en.U*;dO[(#iO|9 K%jIL]lAv "P(>XDO",$:Sc%?~*,&xCtΙZ53Uj19vT(CYF)Xxg?;7]_CKu.io{-j2gC#ېs"$D/Wa5(2.ͤG WN}2``?;kQZi@,lr6QL71|2K`W8,HsQ,+ 8ǮwY VcK@fчCɻI1uI])bnR>Lv#D_D$Xd3zĞJzSdH~/̋I-aAf(qB;&MY(GbN>5A@nlB(؍[YV5@:dbvIuk:n;xRx*\"/tqoEزou?:L*юѫ'(@nRC J%RS9h ¶ߓ575 47?M)+zf:u xMl]6VZ-2Hu,|i ;ʌߘz{%bT,{iM^%xYk|1!qi,MyB=_%[p1{s/Q"X *ojg@nl ź5:ցs"Pt4GA",1IdL,b]cQkXۙS79rq0H'eFcgN[;=>C䑔Vr[9Fr" .N'RU"Sn>]$Q1頥)~V5ym K&DӰB,6b{@wys'e2-"%@6FTTvB<;:h4xay.>ٵ(8^Io-kG ںJNKUi7E4jA,ɧ`4IJؾ6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ث\hm/ H[ ,`@N l+)oPPVN@Xc8"2M0o F=<\ͨVONK!dy{y1!6B#(M= (VDES9$iCCmNWa}Mvo"R;{veS,oTRASW$r3*Aڞ/ ."-j<|0^[F'EK6aRj2+\eqydWkFM4qPIp>#3*QM2jvvVMi݁eDJK |[2!QحYVpLKikffXJLa{EʙsCzm⦹n*d8OmzeU(ejliQL,.-=+EyB .dDqJlG, ;/ylnEjZ?HOl,vCcVZŶ?ꮮ@LmZ+;`8l\^["[YDsmvLڶyqOzdSL%՚CpF i6:G.מW[*o`:Yr?WIO' ۑ#uRY3n3(mQbiN:%z3HP!^d.EVpϚ "Zǽ>c! 7Gtd+tEśK+Un;NKh 4Ndծn3!۰&#}[)Q^@y􆸾WpuC~lծefh I@HH<ѧ]L=D)+,YQ#cJ#)QVY)yT{bÄ6R@$|4 5Ԍ>Ϥ;a%eR@O-it%ME;| ޙls>\r[}sy(yE  R3Ca58Iw$P7bP6SYB`n`99٢NUu(ۗ,解xnFª)̃!Ppn앮'C3DUer$a/M;h SbU9JFGb6[WBޝ [Ax񉋣JF:ڨE*L~Xı^O;lb$*BbK QNHJv-&&fQFeVɤUv(PxF@od'/4zl:+tO\!F;7ہyjĜ齝Mh]ݕY_үm~) HEƝG\m* Izft7ܱJS#xXjK@.ݩ䉑..I˛`_)fWzWZdvgUJTp,0ɽ z:d(1\IH(;S]tnYVz~Ua{IӲ?)#.6[lɞ]+%>+lOƮ94)ـ]ի+Pw nA$''bHvD̯/Kjq׀U9B+켜MG3N(W `?Q59H`FI`0%"EKlikuR!TCcg;rN~\MHn5xAFܮ+L5k#-r0U\N"yw.>-لo!}Mm2m/I] iʲnH ռmLK*0f~Ng e*o ?3[ŒN K^,<}M~1u;Hk=~+[+X#e'Y61I ɄZ1sUCV<B|"Tn#cN=֣~LlY11D40PHAE‹MJ(Ζ%DLlbzm2@\n!rkh6S;Ns휖aR.P2N͊#IrjUSĚ,& ";rvq̛~"Tm6{(g$yZ&% UIh S)@cʝsikqbcV1T=2"u+Aâ۪I( ڹ3 y2]k\h.e3;,`~I4m?5.ķ@.ǩ!nRs/ o,೴cqjwb3&GFnmA'mr}r+Ʉ I7 U~2\G;U3Һ,(>+HOjD@F"LEʎܮ1G;!E|iݍk横d,v9l"vv:{yS,ƻt_zd 0 -?Y[YJ߽2Zg` q.sU8oZv(vحC<[Sr(iv!wt@M`w QH-"9rp;#b[pK{@WQOZJRQFvoPL1ee#c߮U&AQ;>xZbAT92dblA )-u OdY EA2`yQ~vdB@y>ab-=Dnۖ9 l8YNË{v]0J3*>R ;ӃA~.MN X,Nv^ 6Żh2qjz ֝M|kaC}qh1/g4g-y%]yw\mkRc_jh+dz?g4S`Jv/8t{BP~=|;;ܒကxfg]8~jC?Am!Yy[Hxz|]fjp7 h))9Z#u5@hi^[%IYjH48L,2#$HCl5}IRݳM55OLm SnʹE',S5$vse}A0Xo"f!az*9 26*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ث~aC[BUq4MDN"xS FR3LLK1I5Gb`=hz.ҥ!hmEw$ۻhwё'j&ne!Un1[4Nǁ;`#"4RFÙjO47D x#mAmW`P7.Jjs=IY VH#oFyn#A]@w1m+HMs6r .:n61 oľ^a7.<l%") RB:Ʃfı󴾋ӂ0QLo+ɼ&ھwt) HAOtvhڵkznAx:tvN}8!U $9n8j>#h[gwi&#bjI'7mʴ3tn{`1!K[W[Wj v ݍS̺֭.IAJTf~? XJ7yAf!,GbNohly:GDM3MU(F qg33. OSU1!4־1LǑII(n&J6̩-ֺu뷡#FV9F`-L !ثiYZ$AYhz5ˬ1122U"K DvZU c_ ${DƴN+wH݉zaIP4lOOlHاc'KXDPDz|r<,"Q"B.ؓS'(͟+پMZ ޚ8n?!xS-yG:E^jڥQyw-pD8QStr!ML}PA=v]-ʼa4iBR|p7PӮ'_^D"Q)6N͚((GSㆱi\K$FTeB k>8$1Oe_ޓ?(!bn3_N\$ZṰX$Ha8-GB$Kd`̭I۳x@7^#Su L[uӄҕ5;H.I%c?e~rbWMz/J$ƣ> B8]>mƓM-Giz:|>r(gk2Kl#KaK|DgI4pśN[ZZ%J(9;[RD\f;뵻w#!8ڃ14+mZd`/b'b6ORҨQ]ᔫd;K0I>U9Zc49>,kx$Pv-FGDK>_n⹂dDES3zXJv ҎªA= ofrفBZ" ʵ?'S`4..)C:s#y:199RGRyK?AH|s/;o.0$y>UΙhahKڊMC%L}Нޙ4L6IhrCX+]vlUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]vlUK ?()v6}&ਫ਼!)]Ը۰OL}I5?LH}2Zo\]Yxxr#)ABAOo|0MBKQfH`5֛ku(bƇHWcm+h}Rjwȕc#,jXWX|ZMl'F's۱i-"գu]BB2y[Zv,}-jR*onEq^iV<~xZ[>A=\>3T'Ba Dly25]6"x}]$;M6@9vi&݀u*h^;Jz|^逋@4ڳ+SFyM&Lk#U `0S."9$(H5#i@LXð%ґk1h|K,;.e,HE~/ׄv\ZEr*-. bm,7͒*^-:29"k Ʈh&rG/J)ذ;=M[ckNğLfyc;mŁ8H<"CUSC]WMG]#jI%4͊ .]^bBMX{Rǧ…'pf$S4,Y@j?ZxʀI"hV5ֻ`\Fs^m0mVĭw^]Ӯ\#'"姖uň_ s r2H0A8|naz^/";oP:%GZf [*M$ޜX;x"9SAsS,$6|i9ZF<\<{h/|˪"k;8# +)[oKGZyD~ysm@HaPȆQ zQz=[,4ۍSJKw.m$-l6*~J<jڇn5cNH#bޕQ+1H\تBi6Z!Ż0-\Dc&>,ت3LtS^kq)2֓I%9FSTm-^GRK紴EGOn,/US,yZUztyN4%ŝsb%o( Z^!";:tlUyKGMm.M6_?y;.-P3Yگ/N$א6_تt?~Pԯ{G>l}j$"Cu,Y(զfX䎟.Ii^IhdYGj]BҔ͊w2I-d)3ت^K]PhGl"XV}^i^iO|ث/~BEJ[K>p$HRڽlU~AZݥd6Lmd.A$d)rOjoytDмǩhqIj1rx(T6*ثb͊6*ثb͊}1mǖ?&$uNam+6͊}GEѵ̃oCiuem7čq'o3b<}{S]:͕2E$a]:6FPà͊-m<9:|̧6KG6*_>EI9 y=α4kz $YyK%k0p?<ت[-?On5}D_xr͊Ʃ_ڇ4O2Mye˪Osb2~w誎x2]BG!i:ت/޽ޭto2jQWխLB11#6*?_ZNm}"O7 $VSpVc1vӱTߖN[MZAR[/"#NٱT&+#e{ۨt42ȍ+OО"ocVO{"Eyze[RBq BZlUO%L/|G_ѧլeXpA[~ -ث^u}z_.iS\&}o8ھzmFܩlUZY~b~uolڬ:ޙ=+'3w$T_/<}7TCyVߥ'pAn)Y_|I#p3bfE]sa@ūzZ*].y~!>U='+)sCH50G3;iΈ 3"Fr)OlU6/Ҽgɷ67VcNynncfk\| u;dVĶG/f4iI:,bTїAguKdӟ=$ xcc>Uƿc{XiFhaH͵<1; ت[O1k7RN.EmkSL"yەOzUyWΖG_(_jքW)ʗDU"fX L6>9T-?Gҭ_,Zyqr$Շ5̟IāhҎ>9U-+k3-o.__yRHNq,=d1?Y;/JfYe槙$ߔH>(,o޼7}bOޑJ̺urkB`L6!stɷij:a_ɍ|/:E9:zVK(%+DQlUyBtҳh^b볤:HHXٚ; c|6*ϚfWBMR$`"T6*ثb͊6*ثb͊4;Wy7Q]oCM.4>U,%BX#C:}by?M}]i~6s[޳"#r fU-u뉡ikMvLj0Es_DM3bVWd4+{1Ns4N,qJQC͊m{b>tKgi#hŸ~lU,O3k\~hknumvVrłoZЫjVU8yD׬ǧ]'Y{Ij`3Y}+_xٱTo|o} y$g [܀2!'k͊^knֺ׆Com"ݙ+DvWg6*yMoEX56YUBaM3b>l\X=OB)k}>h+}]ecOAhlU02lUٱWf]vlUٱWf]vlUٱWf]vlUٱWf]gv֗TYk7tlgܥJTvVP5۪fYw4?:tЭ5+J]:}6Kg.uy:oS^fXŇ|w] k݉UG 8;ث ?268MPCwi[yfe/~liTO̿tty]妄wzi PIY."rbzWYWco@/F87ʬM{Rثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb͊6*ثb endstream endobj 127 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 62.022 423.2692 Tm 0 0 0 rg 0 Tc 0 Tw [(off)14(er)-245.2(mor)12.8(e)-249.9(sel)12.9(ec)12.8(tiv)13.7(e)-249.9(upt)13.8(ake)-241.8(and)-240.6(A2M)-235.5(rec)11.7(ogn)14(iti)13.6(on)-244.1(cau)11.7(sin)14(g)-248.8(in-)]TJ 0 -1.1116 TD [(ter)12.7(nal)12.7(iza)11.5(tio)13.7(n)-220(and)-211.8(end)12.8(ocy)12.8(tos)14(is)-215.2(wit)12.8(h)-225.7(d)0(e)13.9(liv)13.7(ery)-217.5(to)-215.4(end)12.8(oso)14.2(me)12.7(s)-225.5(and)]TJ T* [(lys)14(oso)14.2(mes)-489.3(eli)12.6(min)12.6(ati)12.6(ng)-491.8(ASO)-494.5(bef)12.8(ore)-488.2(rea)11.7(chi)12.7(ng)-491.8(the)12.7(ir)-497.6(des)13(ire)12.7(d)]TJ 0 -1.1174 TD [(tar)12.7(get)12.7(.)-320.2(Bec)10.6(aus)13(e)-319(o)0(f)-318.9(thi)13.7(s)-317.7(pos)14.2(sib)14(ili)13.6(ty,)-311(we)-321(sou)14.2(ght)-308.7(to)-319.1(pla)12.7(ce)-315.5(a)-324.8(sig)14(-)]TJ 0 -1.1116 TD [(ni)14(can)11.7(t)-174(emp)11.6(has)13(is)-174.9(int)13.7(o)-173.9(eva)11.7(lua)12.7(tin)13.7(g)-173.9(tot)13.7(al)-176.3(pla)12.7(sma)-166.8(pro)14(tei)12.6(n)-173.9(bin)13.8(din)13.8(g,)]TJ T* [(yet)-154.3(gre)12.8(at)-153.2(ASO)-154.6(bin)13.8(din)13.9(g)-156.6(\()]TJ /F9 1 Tf 9.1925 0 TD (*)Tj /F3 1 Tf .9964 0 TD [(98%)12.9(\))-162.3(for)-147.2(bot)13.8(h)-162.4(sub)14.2(set)12.9(s)-162.2(was)-149.1(obs)14.2(erv)12.8(ed.)]TJ -9.1752 -1.1174 TD [(We)-333.9(also)-333.8(explored)-333.8(any)-338.5(protein)-331.6(binding)-336.3(prole)-330.2(differences)]TJ -1.0137 -1.1116 TD [(using)-500.8(a)-497.6(uorescently)-500.4(labeled)-506.8(ASO)-500.2(to)-497.7(study)-495(ASO-protein)]TJ T* [(binding)-198(in)-203.9(plasma,)-197.8(yet)-200.4(no)-198(signicant)-203.4(protein)-204.9(binding)-198(proling)]TJ 0 -1.1174 TD [(differences)-350.7(were)-347.4(observed.)-348.4(As)-348.5(conrmed)-346.2(by)-342(this)-350(study,)-342.9(the)]TJ 0 -1.1116 TD [(tight)-207.5(binding)-209.6(of)-203.8(protein)-210.7(to)-209.7(ASOs)-207.4(suggests)-211.1(and)-206.1(emphasizes)-212.5(the)]TJ T* [(role)-362.8(of)-365(proteinprotein)-364.9(binding)-359.3(and)-367.3(shuttling)-361.6(events)-366(on)-359.3(the)]TJ T* [(hepatocyte)-275.1(surface)-270.1(\(such)-271.4(as)-273.9(the)-269.5(A2M)-270(receptor\),)-276.1(which)-272.6(could)]TJ 0 -1.1174 TD [(seemingly)-249.7(facilitate)-258.2(and/or)-249.8(route)-248.7(ASO)-252.5(uptake.)-248.6(To)-251.1(this)-246.4(effect,)]TJ 0 -1.1116 TD [(these)-353.3(binding)-347.8(mechanisms)-356.5(and)-350(ASO)-350.5(uptake)-348.9(are)-351.2(a)-347.8(saturable)]TJ T* [(process,)-324.1(which)-318.7(may)-322.5(contribute)-319(to)-319.1(nonlinear)-323.5(PK)-319.7(exposure)-321.9(in)]TJ 0 -1.1174 TD [(tissues.)-351.8(Ultimately,)-359.4(hepatic)-351.3(uptake)-354.6(of)-353.5(ASOs)-351.4(has)-349.9(competing)]TJ 0 -1.1116 TD [(mechanisms,)-457.9(which)-462.7(give)-455(rise)-454.7(to)-457.3(diverse)-459.2(intracellular)-457.3(traf-)]TJ T* [(cking)-284.2(into)-281.1(multiple)-282.4(suborgan)-280.5(compartments)-284.2([32].)]TJ 26.5177 20.038 TD [(See)11.8(min)12.6(gly)-366.3(lar)12.7(ge)-377.7(pol)13.8(yan)12.8(ion)13.9(ic)-372.1(ASO)12.4(s)-381(suc)13(h)-381.2(a)0(s)-371.8(ION)12.3(-35)14(338)14(2)]TJ -1.0137 -1.1116 TD [(\(7,)11.7(164)-153.1(kDa)11.9(\))-266(may)-259.1(not)-262.6(fre)18.6(ely)-263.8(dif)13.9(fus)14.2(e)-267.2(acr)11.7(oss)-256.3(the)-263.8(lip)13.7(id)-261.5(bil)13.7(aye)11.6(r)-266(o)0(f)]TJ T* [(hep)12.8(ato)12.7(cyt)12.7(es,)-369.5(bu)15.1(t)-375.6(req)12.9(uir)13.9(e)-376.6(pro)14(tei)12.6(n-b)14(ind)13.8(ing)-366.3(int)13.7(era)17.4(cti)12.6(ons)-366(on)-370.8(the)]TJ 0 -1.1174 TD [(cel)11.5(l)-214.3(sur)14.2(fac)11.7(e)-209.6(for)-204.8(upt)13.8(ake)11.7(.)-210.8(Sin)14(ce)-206.1(A2M)-206.7(is)-203.7(a)-215.4(low)13(er)-204.9(cap)11.6(aci)11.5(ty)-203.9(pro)14(tei)12.6(n)]TJ 0 -1.1116 TD [(mak)11.6(ing)-239.6(up)-244.1(onl)13.8(y)-248.8(a)-249.9(sm)14.1(all)-240.9(par)12.8(t)-248.9(o)0(f)-244.1(the)-240.7(com)11.6(ple)18.4(x)-248.8(ser)13(um)-245.3(pro)14(teo)12.7(me,)]TJ T* [(bet)12.7(wee)10.8(n)-317.9(2)0(%)-308.5(and)-304(10%)-303.9(of)-313.2(tot)13.7(al)-308.8(pro)14(tei)12.6(n)-312.1(con)12.8(ten)12.7(t,)-309.9(kno)14(cki)12.7(ng)-307.5(out)]TJ 0 -1.1174 TD [(thi)13.7(s)-317.7(pro)14(tei)12.6(n)-312.1(may)-305.2(not)-302.9(sig)14(ni)14(can)11.7(tly)-303.1(alt)12.6(er)-308.6(tot)13.7(al)-314.5(pro)14(te)13.8(in)-313.4(bin)13.9(din)13.8(g,)]TJ 0 -1.1116 TD [(but)-326(may)-328.2(in)14(ue)13.9(nce)-328.2(A2M)-327.6(rec)17.4(ept)12.7(or)-330.5(rec)11.7(ogn)14(iti)13.6(on)-330.5(an)13.9(d)-335.2(cle)11.5(ara)11.7(nce)11.7(.)]TJ T* [(Fol)14(low)13(ing)-314.5(AS)14.4(O)-324.5(upt)13.8(ake)17.4(,)-320.2(ear)11.7(ly)-313.4(sor)14.2(tin)13.7(g)-323.6(end)12.8(oso)14.2(me)12.7(s,)-315.4(lat)12.6(e)-319(end)12.8(o-)]TJ 0 -1.1174 TD [(som)12.9(es,)-248.5(an)13.9(d)-254.5(mul)12.6(tiv)13.7(esi)12.9(cul)12.7(ar)-245.2(bod)14(ies)12.9(,)-251.1(lys)14(oso)14.2(mes)11.8(,)-256.9(g)0(o)15.1(lgi)-245.5(com)11.6(ple)12.7(x,)]TJ 0 -1.1116 TD [(and)-471(the)-471.1(end)18.6(opl)13.8(asm)11.8(ic)-475.8(ret)12.7(icu)12.7(lu)15(m)-480.4(con)12.8(tri)13.8(but)13.8(e)-474.6(t)0(o)-474.6(the)-471.1(com)17.3(ple)12.7(x)]TJ T* [(tra)12.7(fc)13(kin)13.8(g)-375.5(o)0(f)-365(ASO)12.4(s)-369.5([37)14(].)-367.4(We)-368.5(pro)14(pos)14.2(e)-376.6(tha)12.7(t)-369.8(alt)12.6(eri)12.7(ng)-365.1(the)-361.7(cel)11.5(l)]TJ T* [(upt)13.8(ake)-184.2(and)-183(dyn)14(ami)11.5(c)-192.3(tra)12.7(fc)13(kin)13.8(g)-191.2(mec)16.2(han)12.8(ism)12.8(s)-191(b)0(y)-186.5(the)-183.1(abs)13(enc)11.7(e)-192.3(o)0(f)]TJ 0 -1.1174 TD [(A2M)-154.8(rec)11.7(ep)13.9(tor)-153.1(can)-149.6(in)14(uen)12.8(ce)-154.3(the)-148.6(end)12.8(ocy)12.8(tos)14(is)-151.9(and)-154.2(con)12.8(se)14.1(que)12.8(nti)13.7(al)]TJ 0 -1.1116 TD [(dow)13.1(nst)14(rea)11.7(m)-186.6(tra)12.7(fc)13(kin)13.9(g)-185.4(eve)17.4(nts)-176(evi)12.7(den)12.8(t)-185.5(i)0(n)-180.9(our)-176.1(pha)12.8(rma)11.6(co)13.9(log)13.9(ica)11.5(l)]TJ T* [(nd)14.1(ing)13.9(s.)-217.4(Maj)11.8(or)-215.3(pla)12.7(sma)-212.8(pro)14(tei)12.6(n)-220(c)0(o)13.9(mpo)12.7(sit)13.9(ion)13.8(s)-219.8(a)0(p)19.7(a)0(r)14(t)-214.3(fr)20.9(om)-205(A2)20(M)]TJ 0 -1.1174 TD [(we)13(re)-510.2(se)19.9(em)18.5(in)20.7(gl)20.7(y)-519.5(c)0(o)19.7(m)0(p)19.6(a)0(r)14(a)0(b)19.7(l)0(e)-510.3(b)0(e)19.7(t)0(w)19.8(e)0(e)18.5(n)-519.5(DK)19.1(O)-520.3(a)0(n)19.7(d)-525.2(wi)19.8(ld)20.7(-t)20.7(yp)20.8(e)]TJ 0 -1.1116 TD [(su)15.3(bs)21(et)19.5(s,)-263.5(an)19.7(d)-277.6(p)0(r)20.9(o)0(t)20.7(e)0(o)19.7(m)0(e)-269.5()0(n)21(g)0(e)19.7(r)0(p)20.9(r)0(i)20.7(n)0(t)20.7(i)0(n)15(g)-271.8(co)19.7(n)21(rm)19.6(ed)-268.3(th)20.7(e)-273(m)0(a)18.4(j)0(o)15(r)-271.8(ex)19.7(-)]TJ T* [(pr)15.1(es)19.9(si)20.9(on)-232.6(di)20.7(ff)20.9(er)19.7(en)19.7(ce)18.5(s)-242.8(r)0(e)19.7(l)0(a)19.6(t)0(e)19.6(d)-243(to)-227(A2)20(M)-243.9(i)0(s)20.9(o)0(f)20.9(o)0(r)15.1(m)-238.5(ex)19.7(pr)20.9(es)19.9(si)15.1(on)20.8(.)]TJ ET q 1 i 191.622 732.019 m 552.189 732.019 l 552.189 455.584 l 191.622 455.584 l W n q 360.926 0 0 276.435 191.622 455.584 cm /Im5 Do Q Q BT /F5 1 Tf 9.845 0 0 9.845 62.022 650.0408 Tm .0275 Tc [(FIG.)-937.6(5.)]TJ /F3 1 Tf 4.8775 0 TD .0244 Tc [(Pla)-6.6(s).5(ma)-945.2(pr)-5.4(otein)]TJ -4.8775 -1.0135 TD 0 Tc [(bi)20.9(nd)21.1(in)15.1(g)-427.1(p)0(r)21.1(o)0()21.2(l)0(i)20.7(n)0(g)-422.4(u)0(s)21.2(i)0(n)20.9(g)-427.1(hi)20.9(gh)21.1(-)]TJ 0 -1.0077 TD [(pr)21.1(es)20(su)15.5(re)-498.4(li)20.7(qu)21.1(id)-497.4(ch)19.9(ro)21(ma)18.7(to)20.9(gr)21.1(a-)]TJ 0 -1.0135 TD [(ph)21.1(y)-594.1(w)0(i)20.1(t)0(h)-589.5(s)0(i)21(z)0(e)-585.9(e)0(x)19.9(c)0(l)19.7(u)0(s)15.5(i)0(o)20.9(n)0(.)-580.2(A)]TJ T* [(0.)18.7(5)]TJ /F9 1 Tf 1.3878 0 TD (m)Tj /F3 1 Tf .5413 0 TD -.0197 Tc [(m)-252.2(s)-19.7(ol)-19.7(ut)-19.7(io)-19.7(n)-240.5(o)-19.7(f)-246.3(A)-19.7(le)-19.7(xa)-19.7(-4)-19.7(88)-19.7(-)]TJ -1.9291 -1.0135 TD 0 Tc [(la)19.7(be)19.9(le)19.7(d)-565.3(A)0(S)20.4(O)-566.2(wa)19.1(s)-565.2(i)0(n)20.9(c)0(u)19.9(b)0(a)19.9(t)0(e)19.7(d)]TJ 0 -1.0077 TD [(wi)20.1(th)-324.6(pl)20.9(as)14.3(m)15.1(a)-336.2(to)-324.6(re)19.9(ve)19.9(al)-325.8(th)20.9(e)-336.2(d)0(e)19.9(-)]TJ 0 -1.0135 TD [(gr)21.1(ee)-655(of)-652.7(bi)20.9(nd)21.1(in)20.9(g)-663.2(d)0(i)20.9(f)0(f)21(e)0(r)19.9(e)0(n)19.9(c)0(e)18.7(s)]TJ T* [(be)19.9(tw)20.1(ee)18.7(n)-536.5(n)0(o)21.1(n)0(t)20.9(r)0(e)19.9(a)0(t)19.7(e)0(d)-527.2(W)0(T)17.7(/)0(W)18.7(T)]TJ T* -.0155 Tc [(an)6.5(d)-327.5(HO/)6.4(HO)-328.3(sa)5.4(mp)6.5(les)6.7(.)-329.8(Th)6.5(e)-328.6(a)-.4(d)6.5(-)]TJ 0 -1.0077 TD .6632 Tc [(d)639.2(i)633.2(t)639(i)639(o)639.2(no)639.2(f0)639.2(.)636.8(5)]TJ /F9 1 Tf 6.1444 0 TD 0 Tc (m)Tj /F3 1 Tf .5759 0 TD .0249 Tc [(m)-639.5(o).9(f)-638.3(I).9(ON-)]TJ -6.7202 -1.0135 TD 0 Tc [(35)21.1(33)21.1(82)-387.8(wa)19.1(s)-398.2(u)0(s)21.2(e)0(d)-389(t)0(o)-388(d)0(i)20.9(s)0(p)21.2(l)0(a)19.7(c)0(e)]TJ T* [(pr)21.1(ot)20.9(ei)13.9(n-)21.1(bo)21.1(un)21.1(d)-323.5(A)0(S)20.4(O)0(.)]TJ ET 62.022 184.422 490.167 .28342 re f 62.022 87.194 490.167 .28348 re f 62.022 155.792 490.167 .28348 re f BT /F6 1 Tf 9.845 0 0 9.845 73.3039 190.148 Tm (Table)Tj /F3 1 Tf 3.0002 0 TD (4.)Tj /F6 1 Tf 1.2496 0 TD [(Selected)-335.8(Protein)-330.4(Quantitation)-338.5(Comparing)-335.4(Wild-Type)-335.7(and)-332(Double-Knockout)-336(Control)-337(Plasma)]TJ /F7 1 Tf -5.3958 -2.8562 TD [(Assayed)-338.3(protein)]TJ 10.7512 1.0135 TD [(No.)-334.6(of)-330.4(samples)]TJ 1.3705 -1.0135 TD [(per)-332.2(type)]TJ 7.5034 1.0135 TD [(WT/WT)-335(\()]TJ /F13 1 Tf 3.6394 .0058 TD ()Tj /F7 1 Tf -.023 -.0058 TD (x)Tj /F8 1 Tf .6162 0 TD ()Tj /F9 1 Tf .7198 0 TD (s)Tj /F7 1 Tf .668 0 TD (x\))Tj -4.1404 -1.0135 TD (\(mg/mL\))Tj 7.7107 1.0135 TD [(HO/HO)-336.7(\()]TJ /F13 1 Tf 3.7488 .0058 TD ()Tj /F7 1 Tf -.023 -.0058 TD (x)Tj /F8 1 Tf .6104 0 TD ()Tj /F9 1 Tf .7198 0 TD (s)Tj /F7 1 Tf .668 0 TD (x\))Tj -4.1922 -1.0135 TD (\(mg/mL\))Tj 7.7625 1.0135 TD [(CD1)-338.8(control)]TJ .8407 -1.0135 TD (\(mg/mL\))Tj 7.0657 1.0135 TD (DKO/WT)Tj .9099 -1.0135 TD (ratio)Tj /F3 1 Tf -46.9264 -1.8946 TD [(Immunoglobulin)-333.4(G)-5754.6(7)-6335.4(0.107)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.009)-3859.8(0.116)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.039)-4533.5(0.810)-5236.1(1.08)]TJ -32.7604 -1.0135 TD [(Immunoglobulin)-333.4(M)-5587.6(7)-5840.2(0.0215)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.009)-3358.8(0.0217)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.009)-4533.5(0.024)-5236.1(1.01)]TJ -32.7604 -1.0135 TD [(Immunoglobulin)-333.4(A)-5754.6(7)-5840.2(0.0126)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.005)-3358.8(0.0182)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.009)-4533.5(0.029)-5236.1(1.44)]TJ -32.7604 -1.0135 TD [(HRG)-11442.1(7)-5840.2(0.0191)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.002)-3358.8(0.0093)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(0.001)-4533.5(0.011)-5236.1(0.49)]TJ -32.7604 -1.0077 TD [(Albumin)-9983.1(7)-6836.4(46.5)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(7.5)-5355(39.8)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(9.8)-6161.2(70)-5858.4(0.86)]TJ -32.7604 -1.0135 TD [(Total)-335.9(protein)-8243.2(7)-6836.4(54.6)]TJ /F8 1 Tf 22.7981 0 TD ()Tj /F3 1 Tf .7198 0 TD [(20.7)-4855(50.4)]TJ /F8 1 Tf 8.5226 0 TD ()Tj /F3 1 Tf .7198 0 TD [(13.4)-5661.2(45)-5858.4(0.92)]TJ 8.7511 0 0 8.7511 70.0157 75.4016 Tm [(Values)-299.2(are)-308.4(listed)-299.7(as)-301.7(the)-307.4(mean)]TJ /F8 1 Tf 12.0951 0 TD ()Tj /F3 1 Tf .7191 0 TD [(standard)-306.2(deviations,)-298.9(CD1)-305.7(murine)-300(plasma)-301(was)-309.3(used)-299.4(as)-301.7(a)-304.5(positive)-303.9(control,)-302.7(DKO/WT)-305.7(is)-299.3(the)-300.9(ratio)-308.8(of)-300.7(results)]TJ -13.7276 -1.0236 TD [(obtained)-333.9(from)-333.4(DKO)-333.7(homozygous)-328.8(mice)-337.4(to)-333.3(wild)-332(type.)]TJ .9134 -1.0236 TD [(DKO,)-329.9(double)-336.3(knockout;)-331.5(HRG,)-330.1(histidine-rich)-338(glycoprotein.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (232)Tj 46.1699 0 TD [(SHEMESH)-334(ET)-338.7(AL.)]TJ ET endstream endobj 129 0 obj <>stream AdobedC       @ s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjz?Nlٳg7槚?<.y/p^EOR0 PUQĊ\899^_F?VoSuc5`Y*?!1͹.!XdR)LK9%L yaJB\zbKS9&dc:CJŷW/7}kTzK֑nU z=<9?+?&^ h>vqV^ө̼("_f+^2~bM$QH~WM( xÊ iMO[MđNyS9$-ă"f.T;) ia''Ǡ+'7? P8ԟS9$i?L)"Z+'O~b*)´|iSrdT_p0@PAZo8_伷 bMѦdREߊ*%H< gA}EFʏao2MMTKIq$s~c JRb04U5\iZf<(q;f??G,$T1UMY0D44a\ayRIoWnH_?+&_gš&JTWj={c_ 9~b%1:R@yl+/7'rFd+"z\Yv c!*Xʆ>Y])*%8 J#"MK|AF'/g H ܡoO |V_ʿuՓWe&8y|@1*'Pr?nøWq}H*% *2~&1$-^@u? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj*sr.? ?Hj?Z72/& 6ڮiIOHS pY8rYE*@˨e@'lFSzm7HbN!(Q_Ȗ_o4/4q]b1K$cRJѻ)Z2TH;7|miΐ+evVWP $7>.9\T;.5Ei `Mpn-b(bdWыrV֠` ?Zh<W&'10Q;n#aj2R=~hd[f tل*q]83|$J) l5+B)%."Y wD1I*9/.5Zw!w.&*K.$Cƌ>=߾K4h-L2bvICHD,>wüٳf bj;lٳf͛6lٳf͜?>t4 L9GP5w Y$ZGÌٳf͛6lٳf͛6lٳf͛6lٳf21] F3y~`l@oZ0:zs-نLJ Ki.nyGSAS:/5[-^ ;'^\&v7#C6lsXZZ\\$WYJ+*"3}ZD1˨\, 3Zy$ wjh/7z2Y%¤-u8VR7>ZԮ㳳G 0xȻ ÜٳfOck1qkˡ^iEn$kkf C0iEWon<:HN"6c nXZ#F:y;MtԴK-2Uf1px#yWnF7w\EpΨjlddbͤ\iE^_2 Z51>ҋ]hyj?.cխ']V-JO{k2f{g?شo_^ѥOLwrp5-SkZ{ItJ̶eP"d޹r 0neW:5]U<p\[Kw2[Di&8r=T5y>6Kg^*d U[e WҼjW~Yk #^%W򤪎 _R4Bvhl͔som~ jf Lՠ|cq =Jo譵kn2"u868Uy[:q鷶>bG4gxZ9Y@Y="oL/!&a^:mǗl{I-֡" u^][V׼o|ui Z걫E0I&19Rh0oVvof|ٽK3Lo}7+䫛Y-65'T*Fqw1qe m7scwvMN.a6N!_Aa<-moRi6f!݃Ս'P[ֱq-NT͠\]WR $z!M:vo;+yzoaMOp‹<37RUĽy-.{c"?[D,f9ĝ m GB״wMR$i,#,$<[c~Zf\ڤWu?pX ĵ_2ZNxRHnJ@,*qϙ]H3C+E)`0HF]K;z`+?Z/^kUӭ{DR7-!Uoƴë {8o-'Q$Eb(XW`;2ֺ<̺o5VD @֭x殑GAcv"S1Emv/9/:-ᆺ5R_+XHc_Kk/,ޟ9|%t'XխZŝY|q1GHOTm_ѣ$ѷbI!x7S+2S{Nc)UOz%*yvwO>P-mg,vO !Tj0yf()4iB9 rC=E^;^MZ\ə/i1$k)|O:v;ᕕ7rA2# 1lٳf͛6ltlM[Pgz͛6lٳf͛6lٳyGZΟƃ!i6ֹIFcz?o*~`yVKLM$Q?4/󐿗ڗSȞrXgV=JncgiCWGy'CD͕zZR\pL:aosߘ^gO+y#Z$?9aORycDf e{;Y<"]?+!w{Ģrݯ#z9-.oOUi@!8"BG ( {K\.lٳf͛6lٳf͛6kb{o5iS"ܟ`FڣĚM죌W!m.QN$vKm0c R@J X}>Zt!4}lA6! 32ǖFF;O,enlf*KUo?B>Yo,+&kwid֔Πm4mHt*ZX5mً]bkYt"MN^,k9-!\rf$5__$Xi>#ukf7^ZS˶eޘ1e~OYHNҗi ;miKޟwow=Ţ줸kAQgEQMyf͜[S51}$<˫ڃH#cDOvCz%-/o,h[W/z916뺛Zk7RSՒݥxPYF 9ZUo7~_YiR-+cYf](ܜ[\\EՁi.b턲Jzp?ӏٗW/|w~ukZzPyܘއ 2Xe",l]T|* ҧJtm6[Nmkm #bHWNժڥ?<-KzܲEZ:a}ONt.nCiFs~!yO#wL,?~u7Z8Hic${uwIB?ִo'lڵ 4#3Pwg~`-Oe[(5M ɧw-^I#J&-AhŬy[=7oshբryC}/Eе\5AKeݵ+NJHR0}`!HPZb@I~}Z s"% O?^Jƒzkh6sY2-WOٚSs<$z 6wckok(a4KJQܯJf͛6lٳؚ6lٳf͛6lٳgϝ?B;Ӯ.am \#GjrYC;~uZn֭{mYNVA_NtVE`QNPKc+A `q$N=3~Yy_7ޅi^A=z *yzHG[2 ";W.T<$xl6ҿ}n9/3Kj6ɵG1S"oMk,EӑDSy~u@q[կ:9,͛6lٳf͛6lٳf½lҢV##޿z4 C=Fy_Ż 8dJ)t?ZiJNm@-T9n8-RzdpϗhgO"z7j"e [~&yrW _4\JHOFgcw=_4FWO1j![ԆH$W9IwZ^AnoJ釨`7 Wf<ywz'42 se!;ˣl,J =dkMpϭVM[2DJCN)R)F$>Gֽ]KMX&\#.j5I.%!r QNriPd{ EP cERãPWo|8( A_3+o-xQAF@TVDEpIM28x_o]¨@/3Rjnx4Wy/ +3E"&V;6lٳf͛6lo&3f͛6lٳf͛6lsOcA Mk]مg?L8͛6lٳf͛6l|cy+[4Yy>Q;$S:\C$̳(B\U$Z?/,{xvY\&P4f zxbǕfSNPCu)- 3Hd+TbE_MbU$- I>,>԰sfHhYȳ[n$ETDT0 _iH0t2,Ф|2(`=W/ҋ5]e_ֿNn+Rh*1ADx<0hMG1aІ3+ 5urt6郊#G28E5QAaBOZٳf͛6lٳf͛6lٳf͛6lٳf͛6lo&3f͛6lٳf͛6lsOcAotM:&{vVՙwBJևqSH=c]URD۷*nɧf͛6lٳf͛9~iyVt}F94d>NVe+wE_TMäVmxVzqhxң#Zg5m?5h/'OQ]YE*RO,-+zO-k[/ԷuqK*$+S|ϥ_(iYL6sBDZK;$nHܺ'4hN(?<>"]\ i/?ZdФhUm]'YLÜA-&/^;l_ LZkMʑDKcTZ6w12ȌSh3F( |٧Mk5WWpGwkvEi`?.yO!o>`mjƤUQQxM;l2W6lٳf͛6lٳf͛6lٳf͛6lٳfȵw ) ;RSG $v$ ڻ<˰ZϬ]^eh,\\7UPI$sucLѴ-NuiS@,ĝG?o k~\0dn>R\~vյ-j皧Ю4/yN}?_UEev&<ԡ0OCW]em:e }}]g*؁?w##;lٳf͛6lٳf͛6lٳf͛6lٳf͛cvrX5eBw;ugkk-?JHHGKEH oF`C1wo*$HaGul۴7~m6lٳf͛6lٳf͛6lٳf͛6lٳaDP򴚯i4FԹ…̨8wQnjz&u젽-ͨ5Ӟ:9ֻAEaqRDQ2[ybI (&4/N-EmPSԚu;uʴH8e{ťD=kȰ~t$?:k֟.x-u Td`(>0g6lٳf͛6lٳf͛6lٳf͛6lٳf2yYǰ]jDK6K{&cf%}g/=FDu+<4I<H@Yݮ' (U^Io Ӽy+6.]fP֗XR"Sw|XNuj Y]c2>|$`1kDdO4;^+ (EY uR7=r=y̺ -W-~tkw.# VmMտ_wٰ>m宁kau){g5uG.P_PZoO#yO9Գf͛t4 L8kȄF\VP\G3T\螡udCA˕@@|06lٳf͛6lٳf͛6lٳf͛6lWuI<`cĤhҘi< h-d4')Me  9RE@>~k?Ϛ-թ#;=Fˏ61끖XRPFjdaFr#tY<6t.uiBD8TkNf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6p]7[V}T޳f5 dCT=9~T|W+ # F]:tΥ6lʿk:;=z6lsOcA#-id5[;Dnj0Qʒt}Uʒt}Uʒt}UWhZfEi46P1I)رgsȷKois. JNɷ4?uj)lLOa+&ӒAͶ_[&ST\$bu)oTR(͛6lٳf͛6lٳf͛6F|=II}<3͑?yNnm;jw= 7gԴo3y~imuGt!9 w U`Jëmvy~dxI1Pdd(~;?wG|ǮE6Xtn#K"||[l8HPơQG@ٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͜Mտ_wٰ&|UP*I(@g :y[:m֛,ѼQ$ !$W=6l|O~tknMoV꺓# x`gZ͛6po(\-3[XA'D"T7>_8]3df[Ҁw͛9yKL5/^i&^Y!夌zW?+;z_BygezB,OzxGf͛6lٳf͛6lٳf͛ 4jz,p}(/3͛Ӻ9UW)сVݫ-hҬ"Jj;x(Xn(0͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6ltlM[Pgz͛jw[iwԆ$J9*+g&jW_ygH ~ц5j6lٳ˿GοOA͛6po(\-3} kIE)O8͛6lٳf͛6lٳf͛6lٱIh^F1i.HhJ8y}n"<~1i^T6B}R.6=.yi vmh{q*|K}[B#ZFRj{qLٳfڅ1r !uIV 5VHXѤ, RgImjobkՕTlٳg#:"~KpߥJ/Ĝ7l뙳fk:w b^ mVV=@Eah\7^Ԍl`C+Ӷ}J/\ؿS6/7h8q#b3}N/\ؿS6/7Ԣh8q#b3}N/ؿS6/7h(q#b3}N/ؿS6/7h8q#b3}Nؿ(B<;{U6K*|z7%F_Ԭ;_L-4fK_ sYF~+#jƮ~f(HXW ͨ2f}Hk_V7֭?oZ\[e}nCjC+V7֭?oZ\dJa.'F|$(Te7DWv!n$_Fh|gE;{v{x5̇7?FBEO4*>ܟGh>+;Q҇ٸu>"A}KOٿ*O(YYx{}dN_??$f\fgmVug$}N/ؿS6/7h8q#b3}N/\ؿS6/7h8q#b3}N/\ؿS6/7h8q#b3}N/\ؿS6/7h8q#b3}N/\ؿS6/7h8q#b3}N/ؿR6/7h8q#b3hQLbv3`=fI#/H8؂Fp/5^Wק׵KRh/HddS%T46l_'yrwox-"uBWq'w\nl؆o nA=x>gpԭ~4.`5u\a8䯎u,ٳf?o9fUOit֐()"Tr;96l]\[~hџ;|!G4. Rc *t#`k`/BzԵ{j11ǘ'^%N[]*4zr+`м[RQB BDW{Wle.ZVhG KrAhwW\&Pz.|R] F-hFOk~m\k6WUXCsĿ@~`ݏ n"cA#\@MIo/~_F'oy)W&ET4|C|a4# |“No5idp(?Z8t9($D~ߖ M :sե{CЪtNм-n5pyrb`lSM|Luoն*V87^y"khf9kQcmynbƺdW̜!GADqh/\n3~7QDKW(ߢ%Fo ?7wћDqh"_G4f/\n3~7QDKW(ߢ%Fo ?7wћDqh"_G4f/\n3~7QDKW(ߢ%Fo ?7wћDqh"_G4f/\n3~7QDKW(ߢ%Fo ?7wћDqh"_G4f/\n3~7QDKW(ߢ%Fo ?7wћDqh"_G4g!0_걙^b<Q6lPi=#?hE&FzK6lٳ7t4 L9Dq.wDce@@=qo*éIG^Z "a،;͛6lٳf͛6lٳf͛6lٳf͛6oROKO3"#R 4#i*Jq|ٳf͛6lٳf͛6pw]u>a'o2E<Է[YdDD:5¹'ӵ̞y8 4VB v'`MǏh_e{ =֬nՅɈI;z6;kƺej6s:K$QUkn25fMB}& }KMv땪qLY_"-o7!_Z@Xzϗ5?2.^>k67WvZk_Qzp:hYG/S0f4MzgWF6MsÙx uNj?3gZYn N5i"qQ`C?1~c"_NM jUU xO5_'Pm :DU-Z;C#a\,cޔN$oPF#/5cɷ|~|.:?աNpbiahr\+_Z=֞"& q0|WQ]v|ӟs.ޝ+Lkz.{^-,!{XԵwc 󁑟H{r[dHSr3<&ͦk\m";1G)u_Ig.ܣƕVvzl:ΙsCʶmK7s?ym|ٳf͛o(:Aqq-ֺK|A?MUS<++KAomoZcSͤ?W dq~VzO}4iQ{~UȻK9fIXGrxOŊ_~Wh7^Gsewr$`+1n#dQT֛ʸf$&SֆdN3_:Ӄێu;ᦅ;Cyb{7dI2$+VU[Mk7ˏM̨a[qH$aq/Mq_*A4%羹u~vX򺀯Z6osޘ)4H 495=V՚ҖM,1YʳALBƯ$G?-'Z{u]R`١flh3xV^[:M}~'.$-gI"I9R7Yư]^265˩=N<\kQZV^7W}$CaQ nefB|6']]Xie΋!G*eY oݭE0˟v.z1fYաv5!Q*\Gs޸Sv:a,5]SOIѕLk FxD@a]ORwP]Y"әMxjh@]t_\.5k=M^Ĩjq61#qǐCE>ineF;SU>}bM]vj~Ty5zVqu8Ԥ#rV'ڃlJFm"K8,i#գ|qȊlߖ9֣QhaS&*"o퉧?!{mM]69Zy q+"pOU'.5&d6lٳؚ6㉨4l瞿##=%6lL%\E_ygfμօo~Ty!HY>J|Ol/_ BQ9Kpk99|T|'ykCǪYjz< ivNNDeLf͛6r4y[m^eVJ]I,"[Tty?,_.P(RH<*S*W |6\P7[Kzsո&X@"{>nmƧ{ybY-͆sERV4M"WhDqMonWcE-Ucl;*RG*?S-SQҴ#Nn5MN=>^m˪j־I5Y]H&_*,Kz-b+|F}gI x/o(Cut+lRi^uxm]f'yJź2ySvg? ,i:d$X\:z$Nג% ͟>cuI6gGwG~0C'.S͛6lP7~uwz lٳyGZΟƃ!i6yduM}p6yrC^a_o%D]ť=­BORG5{.3rKBV4qy~JT/եcu|UУ|ޡVYY%?y$fc3_YI%$sfdkV bx;)7蟖ƹL)`K T_q 嘼E ?jPHY϶:93vUZոֵ(Ka:s %{?ʭHMiium2 y<5J (ۥ(wyQ7h`Z"\ {Li.FyWm>8|sGJ-j[ *Ip'XT=y2)s{|iߢ)+uUHOMd5ԍUW -3hRiˤ%F-I^ `1a[iuZZoۺ,ֱ4#'*j;L-ᶷ (ƽh(͛6lٳf͜Mտ_wٰSզg<8MGbDd'P㞏͛6lPӿ&׮;qZьޚ)xn!cٸck6lsOcA'PhY%B7|Xʡ-I]Gg¦üLy(n'VftGu +59xY3h#,۳ROlgh,Om0t JWψN<:ҹ!pAu+Sp*Y,iOO 1|ٳf͛6lٳf͛6?ޓnWHd85yUgCk%oIQ̑JN,?wS]Sݡ.+XMhz *Kym5n*z WRլ{K;k[]JdіAmSH<@$+\[BCVD˫V$N%KR9!/^|\@qMoS lZ 9&HBD{U1/DժG:֙帧FDe{zci%lpk7<K [Qr,]>RhB[lx%>3y]讬a07IM>! x;SzNxb$Xdcoyf5+$lZz5o.H3k @ZGloD jmٳf̈́ם_YOY?WKxG$I /*C$Gm仒&2hv\y_:޻ƒkLHk$XV8K1#)=y[|š3oI~8ё±RaO\俎a}2;Uϥ Q0>q>OGI44rֺ}ʨf'T%ݜqwS5]BO D.C=O:W6lٳ˿~uWz lٳyGZΟƃ!i6ygk:7kQxalٳf͛6lٳgEY!ic]6[ wJQ %T$i_|hߘ^mNΩ.qo 1\IFoS#6ߚGȞ_-ԴmSR^wZ5.8Mݹkjo-j}c۬"iI=:X?04vO*]i6>(ỷc%>(x;CXoqshfŶqٯ^xXx4HDjIx҅7՗ŭսՏ=E(Yo!E"yF­;HהּYRYkI$Er2g^.{&$:A35 nAn܀m7V -^2Hu*Pڙ-[B=.h>=:"^Kwͳ`|z's?u*h6e:\g^VNPbkJ;lW[F[h-$2F#4fT(*WеfC5[;诬VKv@1(O*AB򗘼.CumokZŕ)yl4q:7 Or\y/,$T,򭵜n*WZOVg}k:yjj[%V`<}:9sg^5>_kg}LKIX!7qI~46-t2^`{"bY FK1dO!H {^i4Kӗdm[βȳ J>Ew5ڞSS嶇] +oPtǣ#0IggdsM~/4[Kj,6:޼*16UYujrzC]?Shuj}; Tb;ۖ'f͛6lى &nI%mukum2OH#`QUIp\[GʓFI`PhEEzc]@nMN2[x4Tkuo1i$. ;lٳg#/έzoVkpo!auYN3f͜?>t4 L8_6g.(#P#tZ?N-I>"Pv.Hwìٳf͛6lٳfȦ7^`![%yC'ApH+EskQ_蚉.eHsۈbIJNw=?ʭQ4m?KBL>eo3n;Ozz9=9Wl>uל<&X KGէIh;@ּդkc"M .[#neWy&wE蟕XhZ%椷_hzE.I?c^eY`6*z֬ѡMz/њqҲ2zM'7Lq[OʝNNlKBߡ=Fy O|[`X?'KK_?/zo%.3ySTvl |uKO iV* 2IXxgZ͛6lٳf͛6lٳf͛6lٳf͛6lٳayBFO,SB6+%ʷ>wxbկ. +P(K Ƒ*qZW?֕Z}0m*yYX#FT'U<\_#3zkB7ı\if9"'ׄ(Y&i#'Num&k`o $zr%Zބҙ?,tvw:b=/Fhx>I-&=+>cA|ZqO vÚHr*#ᓯ_ɟ9yz4 kkQo%w;Fl"|ǜsS̺O\(h!eذ;O/1T<ɥ+h" Rv[?˿ϟ+yOT}ޭ\xed]Ծy>m-N"dPȇ#TTk]S~Ѡ> 46QtSQxomehᓍ%l |bZ S̿XӬQe%-鍺\FGZϜ-t1k>8BZ)-(;?5oA6l.~JLC!1uMGʞaP5G*=h LFlٳyn]cmtGX'$x4ηk[Jx ~C~Z}8ͨybb$xĜYsOcA.$hf*r8//7׶V_V-I0PJ0mĀp6lٳf͛6lٳf͛6lٳf͛!zV>u_6jPs@V?\kk/3IkXM7aj ~qV#;hzX-"UK$"f I/ǬKG>ď2]Œ7*|r)S"! G?큤obcQdw*s_.kf;꥗ :X=`9~O~dOK-;L]5;u`2zmxa?-<Qӕ<ǠC¤!5-Ϳ6Ϻ7 m5//)'+/[\D x*6/-/ o4G"ʥeRvAtlM[Pgz͛!{ $J9bty>e !?/TW),а0Q͛6y]ZC+*M?zw6lٳyGZΟƃ!i6yjuJ?܍5:{alٳf͛6lٳf͛6lٳf͛6lٰW:,6Oj/&,/w7.8ԎS,I-# ZZB:҃?m]J`Ôc_dgf͜>Tkg+Tf$VeY$1&f0g6lٳyGZΟƃ!iܽ[ xxwr(o\jVץk#In}iz?Ό',earf Ga^kMѵ[͖Y%$VDH_d.tٳf͛6lٳf͛6lٳf½S/d <#?p6s$\d:e^Uu+Oڧ^'Ι# u&HS8jTh`dXUO0!EH?jZ8ϧI+`{ot4 L8[Y!0 3OP}PV=(w*jAPxüٳg߶7B2!2RJ^Rs_͑?3~Yyg_2I<>Ґ Yb'Q;f`I]sAbo.yyr-irM" %f0sGmΣ6l==6lsOcA ^:yF✾c͛6lٳf͛6lٳf, |I-ѧP^W׬?5MX(\u\cQ}F$RΛ;DHS}.>snޒrǯ)E a3J.\A0I;gn͛6l؅wp EH뺲ׅh.-(ţb ƻ LhI6Zbdu*.mO)<w"˒XKwIQ`qudjuWF,/6lٳf͛6lٳf͛6lٳf͛6lٳؚ6՛FU TPp_MW;$K8Z硳f͜_tyȃEutҏ%%֒D^>~|Yf͜?>t4 L8LXf@.8hvȾbTr.8+MheO)VR7C%%=b6[)*iT42)2Y*je;yAq_4oO)V2I<KU<¤돧Zo_M TsOO)V79J<~_-7Ք вTSi欤(9`!.VLu<X(8b6_ xXS̬*jޤ4L 2ڪ(%}زyX(jv/ʓR`!AeQRvq,x&@4 ƈ~?|âo#Z@?'1G 1ߧjOcWzjT;-ILjyDu䗑ԊN;-IL/#emH9:*)fT I5EP'8ה"Lh*Mrj>[; ?I~P>V4w?v[\yM[L`r2-C5J)@IFnEk3Ca0ּ^S(&5+jOs8<+23@`jmQ_'%ՓɭRI؎eERI^H=Y2ITOEf,|2PEAM?챲I%D]ٚy2[O)VSA!EfnzO)VQ(+*3W3MSM>,yO%y@?qҼ}iJҿk.SijvnAt#|}<Xo(1`(xMCe-7Ք^IqzTM1/u1YJQu "i?٤(GI%HUrKez~o){ 37=S-7ՍgpsEy4ŗO)VW/(s !}i@XyO%yw7z ĜlSM0"WqTRE~?ߚg5{0%OctB-#h׃F T:lٳ?^M]ߓ-&D]j1e&7!9lٳf0d;77:%Vp^4/ q²2^6*W*?W\IQ|Be yBOVFq ^ro%GU*?W\IQ|?=?JW/&T_7_y77>YWb@?;b?=JZmGOo^so%GU*?W\IQ|=?JW?&T_oPאyCx̻mާW/&T_7Oy7x~zɿW+^Mo]?Iy7x~zɿW?WRߺr1jpO_y7wzɿW+^Mo]Iy7x~zɿW+^Mo^ro%GU=睴2_2}f]B!x& :*?W\IQ|?=JW/&T_7Oy7x~zɿWڇB&|%$3t;|Tsrki|]ro%GU*?W\IQ|?=JW/&T_7_y7'ǔ5ka??=J/&GU*?W\IQ|=?JW/&T_mW赩u 3>}_0GjP2u6n3(cwzɿW+~Mo]ro%GU*?W\IQ|?=J87=Qk~TbTo"MG& W/&T_7Oy7x~zɿW+^Mo^so%GU*?~s~y[yB5R HC.(J֖6XN++^Mo^ro%GUvW+^Mo]ro%GU='ݱu)ڒAW L;wR7z<]iNYm`B,K2w!z竳fiwD9K,$kZU|󋿖p'u/3YMn,SrE)5sf͛8o4By[ɖqR;V0YeW w,ٳf#麿矑tN.n-nV{yEQ£l_u䭕n  ,IZR~5'+;tKXdTI6;m3md}g`/.8G吐bw}v+'O{=. d e'凧M8 zZ(F>qLLIh`I+Iz܊֝Z㭿-!$}1&T'b>*OZ8jiʜCT('Bvߏlj=~Zr"0R$nE:P_VF`Vn GZHĎƇHFdnFCT&S|I?-Ȱ}MwkqbF)(T5~U#j}x#XVO*3uۿ2oǟd)KUj 4ژ,d*F @i+''唗o;ijTZ6uߐ_ݢ~Xf]44̆U!}(k~z2rARx)RAߑ?CcC7SAFcJUl(\ɣA+7* )ݱ -xKH@Ȫ (=BA^qLeMIZ?[B4SnXWCMژ{)qы?펏 hΗ`ޫ(,()mJ5 fu7,_5YR͏+?YۛTgK6?/sʚbEnoS_,ȿ*kM~VԳc"7l_3YRŏ+?YۛTgK6?/sʚbEnoS_,ȿ*kLVԱc"7l_5YR͏+?YۛTgK6?/sʚfEnoS_,Xȿ*kM~VԳc"7,_5YR͏+?YۛTgK6?/sʚfEnoS_,ȿ*kM~VԳc"7l_5YR͏+?YۛTgK6?/sʚfEnoS_,ȿ*kM~VԱc"9痑<|sitV$ ř>Q͛k},lRHdq0BA<4g]qOo{pIr!ڹsf͜__^l>|&&,L2vSћ6l0?/#&v)=OM:z<+ҴڸG1#0YQ/߲q0q=oGoOᇙf͛6lٳf͛6lٳf͛6lٳfͅa.4,$;HF*wVB Y)L_6lٳf͛6lٳfajg1}mRhKubYyjŹ-jZ0q5qC m%"f݋>4F)5zl ?3J+i/!Gmv7j>}6Ww.i .Y"վ)1X|,t7WROF:.WTde_^F;O֡<l$;S4jO=v˪O"o/}[MV{_T^b(&i8A)]['쭵 m;{ˮl#`9sU>q1˹}'izH!t"RE;P8pmlnű1jWIi71q(,OT|.-REk` bdS10Ep֎4/a/~=w7gxe"-/4$2?h~ae5W2iLDU=Ehq븮Kkvmͦ3(,lE . <ͭ^ziEߤ6jmm-xTJ0Yh.VWZ8ҿꊃg/CW[k/:\[zĞ~%>pUuCem$IQӭ )ǓI•xG/f-,a +Aّkw#0.FwŞub#`w ndK x;p3|_ɗEMF%従K &ӧҽ&9rTfUքST:v5)+fbзWO|vj_4Rґ#u@Zۥͭyaz,|1"8)|d.%5)ۇs'V%n5<6y K>o >xr)k}VcT[tʗj lޑNw14SFINliVFBФn4{KH%xa~ q) y/5Hkئ8T3xaGzS&.5](/ẅῺPmVzF8? lecƻWl͛6qOݷG;&l ]&0ɳ|$w(*k ٳg&n~sWdQCu8I&E!g6lٳ~`A_=FLx[Pֹ܅44XczDRùwd4MȲDG<7>kS 2 HȺaHC@Bݱu9omhbH,LٜY'>m1oߴWZv(vZ(gGd!tJp˶Zy.-?vC#r$`~ p1fo4Ă=N tՔ/=~z~~\e9-n#%_M"vR |DrSuoV=*v[e?U*O,E|Ku]:4p3D/"ҽ~URE{Ӷ~ZyGԼg#_YfZKRX­)›7{>_ܷrO*v/2,9ݔALf͛6lٳf͛6l4RzPuA,Z>]X-~[$1Qͩ\XJn<i6lٳf͛6lٳd/Z}CZ!l9 nnxT$VeQ~UH|yYWm7GH*@gXݣW(n<逴=~yKԍG;Kdi(%ĨzP>U/y_[nbhPA# 9_tv6IawxVx*ambHťȊ)zĮxan[ִSqKҖHX޽Ǡ`J{9㶍'יT &^M]F53˧yet.MKWwrw޽=7ɲ5i̤59)ju?<?B^(qc!/NPd9&%4 R#w~yamrm@[Km2yxG?ySuu}hq_F/laq4!Ir= T7* ص2[YG=^| n/f _oNjsɭq}P93fA&svtHc 某>Zt]R!kYry4cFu]͛<=?6l0?/#&vBHSRjڒFtG] 'sH}yBoƦ؟qIQ0HUNyY4k6[E;ւuGWJcX]lsͣK[Aj. `VE#OE_UZyzYmhxkGҕÿ2jSO-y~d5fhV[&YEFX* U+>E$}?׵;(X_ͷA9EqnEyH,V*Q?<a\\Kmy- PKI|8iLztQEI5xV4|~VyyWL4X~^0XPJ?!(=3EGX0m.J̥Q3S w#ZW>۳f͛6lٳf͛6lXŤʢ861k5 j@zϩ){'34͛6lٳf͛6lٲ4<\`qԎSfEsZpI1A;@oГB=_Y>YYiG ULl{|X/H톙\qob(UpdD YkRp)<^ 40'<އzDQiw{M'SizXثiOLIʴq?2hڜ_fm:oDfd7*Bs|;!$QĜB9,v$~.ȭoX5+a#¥Z$(9~$ۯ/_bIkc"\}RR{,IRԼ&a}pv.ԩFYC/D*P{ 8Pѫ4{! d*…GC/[M>XVf{5$ <)xf gwj,jMkp,vg7XnP!cު\_\ΥGmh@WoMdtUD7?e<{ MӏIhe2"Eȱevn_~8yRMe{>.cpH`=5hz6)BJF ~lٳf͛6l?ovLٰMCag<8E(,ٳg%tyzmvxo=II'ˊ~}[:lٳgփka._Uz8on"$nWmiOE)LP*@*E=)[[6_R> b^}R ִZW)FRTro@=$F$QG^^@),ge)e_>D_6lٳf͛6lٳf͛yBM+7@uo+_Tjd ӆf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳgx|msf͈jn/r'3 ߒ%3AZuI/tyt{(Q/bUaI%Q͛6ycZOϞ͛6l㟘u;tH%xFF` _{cV0@{lٳf͛6lٲy0[+{KM7KRBVI7蟙5΍\u=F+)eIGx#Uy778w+Ѕvfb!{(Vjze8ר\ Lmn}9㴼D8y$QYq^knbk]PٳQ@0?Xm)<־ ޔ,r?(X zbΣy7S;(ı *<|p?3jVm4tX"}U@+ٗrx|@'#yikh&(.IiN딞n(%[6j -UO%#}in%kޔz.;9PrEjvVW.!2Y!2Q_z6l[G Whi>)Qd)8i6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6qOݷG;&l ]&0ɳz"!?hG&FzK6lm3X|cH]1Z$*=Aġ;Χ3C|ɩ=2^&2q>Jv0j>`u6"Sa棋;3VO99s:y8vf[2yIBM`#|r@zнN{K簖Ypwٗ}&m$It<qG]ݎLH=|`hD;N3f͛6lٳf͑OOaokrVdj@>?5USLɦ栉^t|x)Lm|s^SKa"ڞ޸<+y-5鵋8&!i9D$ƅhx`/j\%2jݜFXGHҝk+y]3YK0dcE,ĚԀ]#RּZt"[؄Q+XYm:MPEM*C-ڼ~T,5 Mp-5{LMUdR$! _QfoS$XZ7̇Y[:Yb(X2s(|?ԁκ¯YZ+p=Ǖ{c'\V kջxVĉ߶yM<|mB++_K[R[ӑ6 o=K.PjzW~ّ*$M$# K:ęTW8')i6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l/L/in"f,TnYAHQ"ї( +'/{ӄi7wqgi =h{^nq3NPVq ,42IO<9K7D xM/^mC,. \IBVUj4,kƢp;.' 'E@*O݅ofHJ6噖{0#883JM:+{cy-6Bk㍛^~C]m6wwVs mb9Cٳf͛6lٳf͛6lٳf͛6lٳdkʶg֗sx4'ЬrB՘1PWm_n$u6bydK+{k{KN-oKk4-`n"`\ (hMxV}o1Ii 꺵s,("ӡ->%a-n\52bJ9Gn?8ʾX{(xToZ@܅_Q_^~n6mV[A\,6U"ah6|3jߑ?*<ǩ텴<'E95rC8?"2Y޷5(Lӿ.,O}Y81cV]ZBYDjj:yf?__0_\򭝤^qs Φi$FCF)U>~h/-a4n^/VT):Γ6l㟘u;_[YBYDe`9|EiZ1Gmƅގv6lٳf͛6lٳf͛6lٳf͛)*B$Cs"kMkYI-uX8H {dsKΞLOYi۽Γ 3AS$kn$~%5U@ L+8jku_S_13½dȉY%0/uak+5.*QNE47—j:4vC+ȳG |HymEm{ү`Py"w*/Hi.JF-|dUԤ+{'QCH%*D'%^c[ҭâH$X8~>EОޑi4K:]WK,C0ڨ5J90Z iߖ+@HH8!P%1:w ï3}*Acqm}zyFȖ ,d##!8Ӷ8͛6lٳf͛6lٳf͛6lٳf͛$QJdEuxT|K R QdNX{LX!oMN ŇB嵥L41ъG!PYGF:Xa(5+P0 ½c.lRUT.SOn.7q'(w͹]f͛8dǕ $WǦi#vMwkìٳf͛6lٳf͛6lٳf͛6lٳa^ΒXd'0.do,[<2ّdo#g\ٳ=Hq"4 kki'XddX!ƴ*yV]Υq 0YEp 5Fu89X9[j1+MDy(ܴO"8_=Ĭ)no'&cZiװΈ+XӚc` wjdXTAM::s8^e9xTJ0-olE6yJIuU|lٳf͛6lٳf͛6lٳf͛6lٲ/ΟѻG46r Tee 3ygV#.7:_mk_K!ԉ HVixNa{?uO>4?j>l`$m'5ht~/;Xolcԥ}%x_M!۶-5 -KΥb֛: mw喏=\N9vw4 Nx|msf͛6lٳg9%/,Xj_hז IW*[pH30ס~jCeEjGg]zMG`Y~ 빳f90_3Lns̱XRdhG,)39FOᇹf͛6lٳf͛6lٳf͛6lٳf½TSӹJ4ͅzf7 .?vኜ3n\Or^ȇY#ީc'*RoT3ʱԿx$[>Hh&/GAJqCG euUٷD*M [׷-D9}"6&qM>ˉO<_9 )5GZѵMCK^Xߗ)I$MΣ6lٳf͛6lٳf͛6lTIo4(#nGJ5͜7eՊ0QȈA*"vOUp?s edV [$9,k7lRYieQޭQkzy(z a ~п,|7sQߤq2SjO?i[:lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf79)C۶d͛6lٳfK/$]>^Qc4i rHx0&fxa?/=s z"ӯiN7òf70?3aUΝq+ũ!i85bdh=rhcO|<͛6s3qǴ>ǬZ&4Mw,r8Ryo׾pԼudij=;cvUJa寓-| N,!8̞QVٳf͛6lٳf͛6lٳc%)dXX?.ҙn5-FhXm !#3g<,y̥_x^S4R{n"e\R ;ҰQD@_Vr.TN jK4PGntL<򬒧w7t*򇧇YLٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͜orOmQɛ6lٳf͞aַ7aZ|Hlٳ~`A_=FLx#ʰ!s@]G-3P.$Z$bEC޽|pu]-*@z"OYTEQo)QK5J.~t&*Gq]7lƮ`:2zG?5go_?5go_?5jZVXuD[y54鴊Q9_tzqw~zOG7TgkM#9L؝ǵ )uK=:䯋zQ=kO8> zVh-A#L3pk ˾!McOV9QB @2gʲ-R-bo!bJ<`C*Vu7V$EivV'CiiB@v.h+"PWÿ8/j. W*0uf_ct>Q:ޞD& ܦci@Ӆ+3sK"}ԫu~Z/p=Xf9J~9Ni?ҟ_'ZS5 KS7'["OLio#S1uOƑ-5?oG[Lio#S1uOƑ-5?oG[Lio#S1uOƑ-5?oG[Lio#S/xz[D:go_&`siPw{v\]7l?ks}v\]7l;9!<Yy@G"B{ f͛6lOC-wM>JHUƊdEȬ8~pϐU̲ʞhV!!>zcf͛8]dɌ ѬX:P2a^#*=eӤͳE"loBMkF:L׉+GIGM}#ǃgPCIQPXԚA۞Pl`CAZaK)$eQQZaX˛>yti}8R Wf@?5@IZ ,0͎YPX֖Y$D06VfEC5c}K?P'Iwaճ4*́na9Ћ Jb'jƬLο%*aQ]-Q<Pi3:_^\:)jAkZ|: ^6=ZG@ߣ̈Ny(FY۞h$l.ZB+/MZDBߣڝc''/]5_ViH,f~>r ^5i~<*2~X.c#mͅߨdS~t[+N_`k7揗<˦5sZOۏ\=8{k4kgU&Ia}3n{j*@mO ^efݧHۄ۳'+anKq\cQq-4W"}:ds׉kf; *9")Az{j*th+@<˪TB_S"v'R_`kƾ"qmȅc4s~X.c9uNXkSJT y$箟s׍&6k>?/_jE5E%~PSTߞ;0ժo׍[K08iS@_jE5p_MhƦhv-lPJE5REo3 (=*Dh+ADǖ.a S ו%(D\5);>;0ժo׉MBc~)F@4'raSfM"Z\OW&"瘽5:4Ռ2z?BKZrNyuVȨhȻ'I~|FhkyceVi?L?V'֝1&/!VogVi?L?VRIf_ВQ?,?'jʎK'Eв!^- YK4BߡejoE~Y|'jK9 }S^ZӖvH־9sf͛6lٳ1Y^۵lٳ~cF~F$N%t /?umTs~QZ:؞\1%1PmႿF^~QyWKoe].moїt9F^}C_gq]&d u$xTC&tuK*A|njMLGQ2_6G7ߣ/?umTrF^Q7S+4 vܔ"~Q2_6G7ߣ/?umTs~QyW[oMˣ#EXÍ8駙wUB s~QyW[oe]nm_їu9/?umTpU}__KPiF!J0e]nmWїu9F^yW[oe].moїt8_:My "+-#-їt9F^yWKoe].moїt9F^~u gnt`Aܽh@f͛6lٳg&͎$Io.uTYwQ$> 6'_:Ꮮ=z..MBܼќs_sf͛8<Oe^Q!R: QC[;V ) cy\H?k|2-ɍQR{Q% WEZM<,̗),5UR9B >9=F|OPЊ'-ʉq$߹`MMpԶt\ A"Po@9\5߮k[.qtgfLň(hrv\ꐤrjNUUYI^3}?mujw7D(awW&CSS\lB@818b&Bk'c#*YpTBI8;SBMKeH,@ ^&3/Q+$n8ĎG㋻6vဢ` MEv*+0Lƿb}Jrٿ.a(FyI3lû1)?,kWg.!0`GtIȊLU`A|GvZuf򼚌"8[X@U 7.z^RyݬnVIQ('/Zh>*ٳ0^#v;Qn U!֜_[w#PC8/GS|?,x~ff>r< rۮ6O˲t nNT:t⫩}ZD_,A)X| qr9NSVI Vv1|t#n>4_snU ƻ%@ M7r2(_3IQB Y 1OS?5ٖn0; CU0^@ 4ڭϥ$"ܕ9Gkv!M^$po!6=6lٳf͛6lٳf͛6lٳf͛6lٰ˚-&Z)%kThѲalٳf͛6lٳf͛9fkknZ+<+9H-C\3G"L:ts/ ,({'Ki's&䝲A]+N;1|0ZE[i MFb !:⺧uK;McӡJHEZaPON^pMgo힡 \L1 ,pUwVbL&_Z4"J0v#ϴFL&ojZ`Bxe;EKh I:. -"?*+Uz6󶡫?忶[kxnm/^wq^F[~'n5qB^:a\wPe$oT0C+ OD:cjCHɑ&i֟k;]65mN}FهG̠x$~_ 5-R-tx2+^$ ѥdļkHMAR;-q(5 )Jy{+Wԯuy|t#k62?@%a?ȕF}C3ڝ_ӵd W%hSpMM[Z-Ύ|k8ʰdY$!alaegQo>g[O6Z$Ick{cr\^4`#}>oyF];i4atsB- G]5j{qeeBO{x"V+El mrX*i^)%B+ 3@|tٳf79)C۶d͛6lٳf#͏8hXM.lqA&YeG%j6Aߘ:2|+{i,5]K2}[D*ʿgf90_3Vp_w\0X0륢k`ATOhJkִhUCHz68zϘOʅ֩'i,V8S1w^/3~Z|1FG x bw=_7yRmvr^8g"2«.[Jy+%XFJ CNJO[Ro4ywe[=yHYSRiVwn>Vՙ/ #EEw>W|-;I򥦬ɤjFL"Y*9adg$o0jM}p$4 Qxro>x#ϗuZ~ک6e} 9f "x-^l3vk妷d GrI r!?^w6lٳf͛6lٳe;FbhIL1}5"8JoIsf͛6lٳf͛6l[vBƨaےii67H.n.K'FJ{SȚ,v"Qp["]*0~[&s_+4꺄 Ps!]7u )xbՎbK}YH8;Lfҥ#Gg/"fJ,Z[3\\hMR1NL얭>xo.A*5'(K3"+[BA}C'ٚ[%xđE9n(u\y)xdK{^Z%[v X%'shS}FRi{efhzL D ۵v8>?)hI:+iZ;7!ʕ/AM خ{{i.mcӉ 'N,]s^Ym,cY9#[\SGڭ^ ]N;JOu=%ftZK+XՖ{oUJ8ЂT2-_W3 L⿴@`򦒷~KlL&ޣVp<>HḂh__K[ꒉC^wL-7k鄺f h3f͛8dɛ t?zoks|:͜%nD&G|x?&mΧDNEw"@8mqEֳ52y8v%=WMpc!aGQ$h wl>#γ__^k^I#>Sry7G7n6չ#4c:Z_kk@>Ieߎ2Ѧ.9uɻK&ޛtg69k7ÆIo\7 ")=*C9;/,5;D<xDҿ.m~KyM,r%AWӝ6lٳf͛6lٳfč}*a^N,J |!r?f͛6lٳf͛6lٲyShFf*L CA5?lFj%^f2tK FUHFY_xZWh>`˚%ǫ{xuR+{vQAwk)WORךuK.h6LG[6xnK' =OE]| W_=izu^ֱK-8[ո`7 5|w鷗\464Ў` )쌘zZe1^* Ug nK19.ZayIkB&fw"2)׌OMK̗Zyu !+h4*ԗjQUia WRE= 1L: 7/ŔM$ȠTbP?E<߮뷑4^0"eFJ+'Ե jwgPYQ䟋:ZCҋ]_MӬwrXZqF{kMO%H0#;y<5݌z˕%ݣi#*Cʵejqm_vܽ݁Y.56z;ʼv,Q_&BަhҬ$ĩY ͛6lٳf͜orSmQɛ6lٳf͞vg,'Yv=VNgX$/4\~kyO}7QKZ^ڠN2ܹ);f90_3m+R=sv;EŸ1WE%uΡK$hMAa/*p=kO@^Hϒr5ycȾY4+gcXDҼlԧ"+A{/-kC%2i-d|$C#P閂;yy#47Z4hn~Vܴ1.!yݤ˓ˑg&QZCN\^Vf\N^BήC#ps_ZB[MvYuxZq8  8 ߖ-wMY 5Y.ҷ@ 忕Ȇ{ca"9]tf͛6lٳf͛6l+$ MYKeH-h.N'?tZW3f͛6lٳf͛6lHSfvkumI-M8}i=F=OVQQW5f:Dt(+8s?%~mח%ִ-]?M-ɵ.HB9r`ƿoM4-*+KGA)udJ֎zx!iTm5[۰WX&G#`-:@~`ӵ.\~I P閝BG.\Eώ3_jt\{q}n(ȥh>/[:IT+dW6X#Ng>H-z/0q@CB$Xʁ@{MR귏~a-l~,*{yFP&u&OEG&-8qWl7kk#zsUWCCQU`AEeMK[Xj>q2M8` lru ƣ>f#QEjJVI@R8h"sJlx YtN-VÄhQQHi k;I^+V(bP۩ة?8bH^1ơG@(;6lٳf͛6qOݷG;&lٳf͛6r_9~Qty{ϯAi&*7$UoQiԧ=0*_2bg6װAk&{y$=c|yf90_3Vj:gmRcW(5f;Tm4`Zi 8B ~8y6lٳf͛6lٳf͛6lٳf͛6l-#opci[--UEwԳ!FW~_Ho՗u-nUx=CQlJchn/'ɥILQ߹]-n^ ea,{Kl%$Q7U]NS}}FddG}rcMJtzwi6qMm˩ٴ|h xܚ͹*=ViϚ5[X.zEǓ#F f"z|ϪkPⷠ!T†޽%iSZ_ϔa3ǍAH3f͛6lٳf͛6l?ovLٳf͛6l6F6_~|tO:~yyWDg)M89{׾Zm>cRS@>XlZ.|zy #wU0?3m( k@:wÜٳf͛6lٳd [uuH,4.-Fq 2,蟙MƍϪZgi 򲤎#M_aŚG;ZCpQZ NRE:]κvm{pb-o$E7$ "v,72͚EVmk6ⴕ]kp~Ѧۃ-9m6o@"4Թm?Z0Om*SFKT%6?,dּ RS WrAlDĒkI坂-{Zoк[܏C}E%$Ec$"" (f+pJR<ǮЎ]6lٳf͛6lO-OjͥOaok"X$BޙI_5U54,njH$ƉL ^)-U\|vm~&?j 'wkkk6P/"2r0I <0}痵{-k]6h{]B # TY$=:m\ {o1˦khK0A@ X{5 ;{?-kzIJ^"](%% /|~cZ2iחK"Sb15ngy/[_km3R=Ud'c6k+yYl㲅u3- 'ΆGϕbjdo3.%>.n~\yW׺,6q]@u{M@Ω[D >%B)=;Qu moBL2h Cnc691i~Z c=kY w?-#E4VY]#fVx-[1ya-sޕxOP ڝ}_<i}y`7#HLJk“BX8[:̫;wS_7o{A<6˰y>JcNѼcLAԧX$KzYԼɨck,xys__iZ}ΛC$׷ }^5,K*@~ɯ]q1%d}H"8 WxY?Uwپ*S؝y#g>u5Kr\ZiTI 8=2=Z7^\/ _P3-hLg|C7s,f A/.49_ߜH.&m4#] xh$,N]wCH֣i^k1C],@6-q?:&,5 @I=#ŏ_<9~mތ<}ђ2Oo<C|l?2<:]i\%ukYD@P|ORYk]?o&뺸}R%1w'#u;4#&"JKCw#FL[f͛6lٳf͛6lٳf͛6l+'42RZw2cn>ˣ 2:e c?]gGMGiяlh>`|ê跱_\0q;Ͷ^h彷KYn,oqm!~$>a?3½ ouXe ,sK4۫v.x^D )VAyfO)-4P@8/\;2+5+ (>V0f&9U ˋɖԺymэtLKYÕ7K0]_Y]4Ϋd"ۀ jj(p'KꚊ^\[oPUrHyʽ;m*Y^ޫ!dkYleTT2~&OkKM>{.ţx,C0,eA rH3f͛6lٳf͛6lٳf͛6lٳf͛9??u0׬%-O|-"[$̖B߉,v\KΟ~~UҦuޒ!y -̅]C=\ɯ.zd-5+:xMWyH lrIڜ=pq'K-D$7OȐ[dߕGmZjfYeE(7؏Lw,YO:E$s)gwC^5jLPM/mC^ުr?+I4cy]f5[E͵Ϯ}rɩ0 M[X_o *H 0=r-?]J;$)D7RQSpt'rJrÏ9s= %XZaB +~.iW֝uIyw[I4uB.sY]/HҤei #|m)䦴Le&V oDe{{ >Q~mff-fJ25ǫ4zt?κF'[w ^Rt<zy{̇VĈ 7殗@4ZCc]6lٳf͛6lٳf͛6lٳf͛6lOyzn}|!RdtQRȪޘ3Hִb^Wq^ڒWօeꦝ836lk>yeg}t:oPeҕU9)C۶dͅ/~_A CRc)է:Sne6lٳf͛6l㟘u;u{ hgs;*u0"?ke<QԾXy6lٳf͛6lٳf͛6lٳf͛"'SI/鷓JKI,HORYp?&*+iv$ d6 .!pWHSM{Wk1_A<(*daT+n6pf54MSK&{8ZUv9kNbY%D'PQPx6tK6BT;w$JF++z NAVhujċ /骑ZPkjڶ>`TeK~1PfEH`Vn6lٳf͛6lٳf90_3](zʆOYf͛6lٳf͛6lٳf͛6lٳf½S}WGS֕2Z?kib'6G} i"d[3&7tgV<,\# |.:xF3K-=AkqU~&=|͛6lٳf͛6lٳf͛6lٳf͛6lٳa>-ZzOB!%bAE?,ŤIŦ[GLyKhFjɩժ7O˟/4ưu}5*3ɮ'-Eȷ5(CZ)g+Y]Y]CqDmeZƛ집QO,3)s14:Ϊ"UݘaG;RXqP;gkJDFb`#$7l;u$kK\ɬiC3lDY&oIQ~z=viZ7+kȒx[0/6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳJ>P93f͛6lٳf͛6l㟘u;l%ҖcO56~f͛ 3f u_>eA?&|SJ8a4= nd{%BaTtٳf͛6lٳf͛6lٳf»뺜ư[ؔVfO,(@Nc\Ӽ,~$c"fYT~SBP+0)~tfq*,<>ga\V!vZ&u{ +˻d,>lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳgx|msf͛6lٳf͛6l<0?3](Ǯw6l:͛6Fy1jpj\&;KVY&~G]Grz4K+38Vgf,s t]E,:3)okbcxēsf͛6lٳf͛6lٱ4(8I"Wp|5oks8aUeN=b(-{v @N 6H#XҘloIuy4_,wF, 8cpc;8EP*|=zx6!y2s&JQI +x47MV5(oԴѷz5AMFt#-9afiZjz9U术[֟ӗ[#croWi?i]9_V6?/vF4 kr*5i=X Z`?,N_m7i6sLeiX)OӍ_NY-?KLcE_a]y}8ތUyjz|p~v+ы挿B?KѕZ~2/?FoB?KћЏ4eb=5yO8挿B?Kє!^RC1!Wh#pȿ!E[׺o!6lٳf͛6lٳf/a+o+yzMXW+>٫G+k-?O !wy?儓OH#Z\-?d~h1T9k#SGQS_?R~bg"OgU8Me?A؎ce/7zUpPj~ӻ*32YZcOoU_U.h1yo_7; d~h1T/{'SU%bvY?4?Y_3N.b=ePc`UԞUB,`,I~q_?4?YC9K0pXՈqRiMu+#G-C^?$8Y?j$K)?13x;8}XŜEX*2,,)^&1_: N XaoʷEByqOlQ13J;\_?S~bg59~S9*hGd~h1T9rTIqQY?j ,zm^;U6 Rȸ~dP5jXEg̖oqU,2Ъ\$ ZV}Fb#EےHVA; TP۾9;|yZ8@H'q̓7O'j~ų%\\IP 7H&h]bx*BI7eh-i1*~PFէ ooRNNSEf?)RΥ_OU.Y?4?YMN *ЎY?j ,y͉O@A 54Ƿ%po?W_|S:S1ZxWRˏwE s {Y?4?K)13/;CI7׀e/KB0h|iM7ϟ6ު3F|y ~gvL+#@z?R~bg_wUQEPߘߙ[ʑB P~T8?Sbg:we4.d~h?wݼ0o60pJڢ)}8a+#G-C13+g,e~/VGZK+V/>ߝ8+C+ePce_Ň;jrnb+Y?jF4<~nZIp~Y4;Gʃd~h1T9TrjY?4ORe'7z(EuU813J;.?K/VGZK!^gOO7ZDZd`OBR^pٳf͛6l endstream endobj 132 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 69.7323 429.3353 Tm 0 0 0 rg 0 Tc 0 Tw [(Histological)-391.3(examination)-385.9(in)-388.2(the)-384.7(liver)-387(from)-385.7(other)-386.9(murine)]TJ -1.0137 -1.1116 TD [(studies)-314(using)-310.7(similar)-309.8(ASOs)-311.1(reveals)-310.6(that)-311.1(6)-168.1(h)-306.4(after)-313.2(subcutane-)]TJ 0 -1.1174 TD [(ous)-193.2(administration)-192.2(most)-189.9(ASOs)-190.1(are)-189.9(on)-186.5(the)-194.7(cellcell)-193.6(boundaries)]TJ 0 -1.1116 TD [(traversing)-289.8(through)-284.3(the)-286.8(membrane,)-288.9(and)-286.7(by)-284.4(24-h,)-290(the)-281.1(majority)]TJ T* [(of)-209.5(uptake)-204.9(is)-209.5(complete.)-207.3(Nonparenchymal)-212.4(cells)-209.5(as)-204.8(a)-209.6(much)-208.4(more)]TJ 0 -1.1174 TD [(compact)-219.9(space)-221.9(are)-218.7(saturated)-220.8(with)-218.6(ASOs)-218.9(while)-215.1(the)-217.7(majority)-218.9(of)]TJ 0 -1.1116 TD [(ASOs)-270.7(distribute)-265.9(into)-263.8(the)-263.8(cytoplasm,)-264.6(as)-268.1(a)-261.4(much)-266(bulkier)-268.3(space)]TJ T* [(capable)-421.4(of)-411.1(holding)-416.9(more)-415.7(cargo.)-414.4(Based)-417.6(on)-416.9(our)-412.2(histological)]TJ T* [(ndings,)-396.8(a)-393.9(qualitative)-396.4(difference)-395.8(in)-394(subhepatic)-394.7(distribution)]TJ 0 -1.1174 TD [(may)-391.6(be)-395(seemingly)-393.7(related)-391.6(to)-388.2(A2M)-391(knockout)-390.3(and)-396.1(could)-386.9(be)]TJ 0 -1.1116 TD [(associated)-413(to)-405.5(suborgan)-407.2(uptake)-406.5(saturation)-405.2(processes.)-407.9(It)-405.5(was)]TJ T* [(evident)-275.2(that)-270.8(the)-275.3(kupffer)-273.7(cells)-272.8(were)-272.5(rapidly)-274(saturated)-272.6(for)-273.9(both)]TJ 0 -1.1174 TD [(the)-373.2(wild-type)-375.2(and)-367.3(homozygous)-376.1(subsets,)-374.7(yet)-367.5(qualitative)-373.4(dif-)]TJ 0 -1.1116 TD [(ferences)-295.4(in)-284.6(the)-286.8(distribution)-290.1(and)-286.7(accumulation)-290.2(of)-290.2(ASOs)-288(were)]TJ T* [(observed.)-475.1(We)-466.4(suspect)-470.6(it)-469(is)-468.7(possible)-470.6(that)-466.6(the)-471.1(greater)-472(non-)]TJ 0 -1.1174 TD [(parenchymal)-392.5(kupffer)-388.9(cell)-387.1(accumulation)-388.1(for)-389.1(wild-type)-386.7(mice)]TJ 0 -1.1116 TD [(could)-542.5(accelerate)-543.5(the)-540.2(clearance)-546.9(of)-537.8(ASOs)-541.4(before)-538.8(reaching)]TJ T* [(productive)-324.6(compartments,)-327.9(while)-318.8(in)-319.1(contrast)-322.2(a)-324.8(greater)-322.3(distri-)]TJ T* [(bution)-196.9(into)-194.7(the)-194.7(cytoplasm)-192.1(for)-193.3(the)-194.7(homozygous)-197.5(subset)-197.6(is)-192.2(closer)]TJ 0 -1.1174 TD [(to)-284.6(target.)]TJ 1.0137 -1.1116 TD [(Shuttling)-257.9(more)-260.2(ASO)-258.3(toward)-262.2(nonproductive)-258.8(compartments)]TJ -1.0137 -1.1116 TD [(causes)-412.9(poor)-401.8(intracellular)-411.2(trafcking,)-408.5(and)-407.6(the)-402(ability)-412.6(of)-399.6(the)]TJ 0 -1.1174 TD [(ASO)-459.9(to)-463.1(reach)-458.2(its)-458.4(intended)-460.7(target)-464.2(is)-457.1(hindered.)-458.2(Ultimately,)]TJ 0 -1.1116 TD [(higher)-434.1(resolution)-432.8(studies)-435(such)-431.6(as)-435.1(matrix-assisted)-435.8(laser)-434(de-)]TJ T* [(sorption)-509.9(ionization)-509.2(imaging)-511.5(and)-505.6(select)-511.3(microscopic)-512.2(tech-)]TJ 0 -1.1174 TD [(niques)-554.9(are)-558.5(required)-552.6(to)-555.3(deduce)-557.3(more)-553.9(critical)-560(details)-557.4(into)]TJ 0 -1.1116 TD [(suborgan/cellular)-208(distribution.)-201.4(Additional)-203.6(investigations)-208.1(with)]TJ T* [(other)-461.8(ASO)-465.7(chemistries,)-463.7(including)-460.7(modern)-464(targeted)-461.8(conju-)]TJ 0 -1.1174 TD [(gates,)-207(may)-201.5(be)-199.2(useful)-203.5(to)-203.9(elucidate)-205(models)-204.8(to)-198.2(further)-204.7(predict)-200.3(the)]TJ 0 -1.1116 TD [(role)-190(of)-186.5(A2M)-183.6(in)-186.6(the)-188.9(PK/PD)-185.6(of)-186.5(various)-187.3(ASOs.)-187.8(Structure)-185.1(activity)]TJ T* [(relationships)-454.5(may)-449.2(be)-446.9(explored)-449(to)-445.8(reduce)-447.8(A2M)-448.6(binding)-445.7(to)]TJ T* [(more)-254.4(effectively)-259(bypass)-249.3(nonproducti)-7.8(ve)-251(uptake)-251(pathways)-253.9(and)]TJ 0 -1.1174 TD [(increase)-502.9(potency)-499.7(of)-503.3(ASOs.)-498.8(Targeted)-503.2(delivery)-500.9(approaches)]TJ 0 -1.1116 TD [(have)-225.6(been)-225.6(used)-230(to)-221.2(reduce)-228.9(nonproductive)-224.2(uptake)-227.9(pathways)-225.1(for)]TJ T* [(ASOs)-455.1(while)-457.1(enhancing)-451.3(receptor-specic)-462.2(mediated)-457.3(uptake.)]TJ 25.5097 37.8528 TD [(This)-351.1(effect)-355.7(may)-351.3(reduce)-355.6(A2M-ASO)-350.9(interactions)-356.8(and)-350(restrict)]TJ 0 -1.1116 TD [(shuttling)-280.9(of)-278.6(ASO)-281.3(into)-281.1(productive)-284.3(uptake)-285.5(pathways.)]TJ 1.0137 -1.1174 TD [(For)-262.3(hepatocyte-targeted)-277.2(delivery)-264.8(of)-267.1(ASOs)-265(using)-264.6(GalNAc)]TJ 7.3823 0 0 6.5614 546.2361 405.7511 Tm (3)Tj 9.843 0 0 9.843 310.8472 396.4534 Tm [(conjugation)-510.2(strategies,)-519(ASOs)-512.7(have)-507.8(demonstrated)-513.3(stronger)]TJ 0 -1.1116 TD [(binding)-249.9(to)-250(ASGPR)-249.9(as)-250.8(a)-249.9(greater)-247.4(afnity)-250.8(receptor)-254.3(compared)-255.4(to)]TJ 0 -1.1174 TD [(A2M.)-238.9(We)-241.8(compare)-248.6(this)-240.6(as)-239.3(a)-244.2(competition)-240.8(for)-245.1(ASOs)-241.9(regarding)]TJ 0 -1.1116 TD [(binding)-463(to)-463.1(A2M)-460.1(and)-465.2(ASGPR)-463(present)-470.7(within)-462.9(hepatocytes.)]TJ T* [(Based)-360(on)-359.3(internal)-362.8(data,)-355.9(we)-361.3(have)-358.1(explored)-362.6(a)-359.4(separate)-364.7(set)-361.5(of)]TJ T* [(experiments)-253(using)-253.1(GalNAc)]TJ 7.3823 0 0 6.5614 418.2235 340.044 Tm (3)Tj 9.843 0 0 9.843 421.9085 341.6881 Tm [(-conjugated)-257.7(ASOs)-253.5(to)-250(investigate)]TJ -11.2833 -1.1174 TD [(pharmacological)-409.8(differences)-414(related)-408.8(to)-405.5(the)-407.8(A2M)-408.3(wild-type)]TJ 0 -1.1116 TD [(and)-482.5(DKO)-484(studies)-486.8(with)-483.6(unconjugated)-489.3(ASOs.)-481.5(For)-486.9(the)-482.6(vast)]TJ T* [(majority)-334.1(of)-336.2(treatment)-343.3(groups,)-338.1(\(4)-330.5(out)-337.5(of)-336.2(5)-335.2(subsets\),)-341.2(pharma-)]TJ 0 -1.1174 TD [(cological)-209.6(differences)-212.4(between)-208(wild-type)-213.9(and)-206.1(DKO)-207.5(mice)-209.7(were)]TJ 0 -1.1116 TD [(not)-441.2(statistically)-444.5(signicant.)-443(This)-443.3(observation)-446.5(suggests)-441.5(that)]TJ T* (GalNAc)Tj 7.3823 0 0 6.5614 343.6724 274.2802 Tm (3)Tj 9.843 0 0 9.843 347.3574 275.9243 Tm [(-conjugated)-257.7(ASOs)-253.5(have)-260.2(reduced)-253.1(afnity)-256.6(to)-255.8(A2M)-258.5(as)]TJ -3.7092 -1.1174 TD [(involved)-413.4(in)-405.5(mediating)-417(ASOs)-414.7(to)-405.5(the)-413.5(endocytotic)-413.4(pathways.)]TJ 0 -1.1116 TD (GalNAc)Tj 7.3823 0 0 6.5614 343.6724 252.3401 Tm (3)Tj 9.843 0 0 9.843 347.3574 253.9842 Tm [(-conjugated)-269.3(ASOs)-270.7(have)-265.9(a)-267.2(competition)-269.6(at)-268.4(the)-269.5(site)-270.6(of)]TJ -3.7092 -1.1116 TD [(uptake)-251(within)-255.5(hepatocytes,)-262.2(whereby)-252.8(more)-254.4(ASOs)-253.5(are)-259(shuttled)]TJ T* [(to)-319.1(productive)-330.4(uptake)-320.1(pathways,)-326.4(by)-324.7(ASGPR-mediated)-328.1(deliv-)]TJ 0 -1.1174 TD [(ery)-465.2(for)-458.2(both)-465.3(groups.)-464.8(Hence,)-462.6(modern)-464(targeted)-467.5(conjugation)]TJ 0 -1.1116 TD [(strategies)-423.4(reduce)-419(the)-419.3(effect)-419.1(of)-422.6(A2M)-414(binding)-422.7(and)-419.2(shuttling)]TJ T* [(involvement)-200.4(on)-198(ASOs.)-199.3(Based)-198.7(on)-198(this)-200.3(combined)-202.6(knowledge,)-201(it)]TJ 0 -1.1174 TD [(may)-414.6(be)-412.3(better)-418.1(possible)-413(to)-417(enhance)-415.6(the)-413.5(design)-416.6(of)-411.1(ASOs)-420.5(to)]TJ 0 -1.1116 TD [(reduce)-188.6(A2M)-183.6(binding)-186.5(effects,)-193.1(reducing)-189.8(A2M)-183.6(receptor)-190.9(binding,)]TJ T* [(and)-390.4(offer)-398.2(greater)-397.2(promise)-395.9(in)-394(improving)-391.5(suborgan)-395.7(PKs)-395.5(and)]TJ 0 -1.1174 TD [(overall)-281(potency.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 310.8472 127.9559 Tm (Conclusions)Tj /F3 1 Tf 9.843 0 0 9.843 320.8251 111.5149 Tm [(It)-336.4(was)-345(observed)-339.2(that)-345.6(the)-338.7(absence)-346.2(of)-336.2(A2M)-344.9(facilitates)-345.5(pro-)]TJ -1.0137 -1.1116 TD [(ductive)-338.6(ASO)-338.9(uptake)]TJ /F7 1 Tf 8.6338 0 TD [(in)-336.4(vivo)]TJ /F3 1 Tf 3.1333 0 TD [(as)-337.2(demonstrated)-340.5(in)-336.4(our)-337.3(PK/PD)]TJ -11.7671 -1.1116 TD [(ndings.)-229.8(All)-223.3(DKO)-230.5(mice)-232.7(were)-232.2(viable,)-225.7(healthy,)-232.6(phenotypically)]TJ 0 -1.1174 TD [(normal,)-461.8(and)-459.5(capable)-467.5(of)-462.9(breeding.)-463.9(Our)-459.2(experiments)-466.1(estab-)]TJ 0 -1.1116 TD [(lished)-416.8(and)-413.4(conrmed)-421.1(several)]TJ /F7 1 Tf 12.4122 0 TD [(in)-417(vitro)]TJ /F3 1 Tf 3.5077 0 TD (and)Tj /F7 1 Tf 1.8604 0 TD [(in)-417(vivo)]TJ /F3 1 Tf 3.2888 0 TD (ndings)Tj -21.069 -1.1116 TD [(regarding)-231.2(the)-229.2(relationship)-234.7(between)-231.1(A2M)-229.7(and)-229.1(ASO)-235.3(uptake.)-231.4(In)]TJ ET q 1 i 59.754 732.019 m 419.868 732.019 l 419.868 458.816 l 59.754 458.816 l W n q 360.113 0 0 273.203 59.754 458.816 cm /Im6 Do Q Q BT /F5 1 Tf 9.845 0 0 9.845 432.7369 666.9919 Tm [(FIG.)-785.9(6.)]TJ /F3 1 Tf 4.5665 0 TD [(Pl)21.1(as)20(ma)-764.4(pr)21(ot)15.1(eo)19.9(me)]TJ -4.5665 -1.0135 TD [(n)21.2(ge)19.9(rp)21(ri)20.9(nt)20.9(in)15.1(g)-743.8(b)0(y)-739.1(i)0(s)21(o)0(e)19.9(l)0(e)19.7(c)0(t)19.7(r)0(i)15.1(c)]TJ T* [(fo)21(cu)19.9(si)21(ng)-393.6(an)19.9(d)-409.8(S)0(D)20.4(S)0(-)21.2(P)0(A)20.4(G)0(E)-395.6(u)0(s)21.2(-)]TJ T* -.0202 Tc [(i)-20.2(n).7(g)-257.3(i)-20.2(mm)-20.2(un)-20.2(od)-20.2(ep)-20.2(le)-20.2(te)-20.2(d)-247.9(\()-20.2(al)-20.2(bu)-20.2(mi)-20.2(n)]TJ 0 -1.0077 TD -.0197 Tc [(a)-19.7(n).2(d)-423.8(I)-19.7(gG)-19.7(\))-414.1(p)-19.7(la)-19.7(sm)-19.7(a)-415.6(f)-19.7(ro)-19.7(m)-414.4(s)-19.7(al)-19.7(in)-19.7(e)]TJ 0 -1.0135 TD 0 Tc [(do)21(se)20(d)-565.3(W)0(T)17.7(/)0(W)18.7(T)-572.3(an)19.9(d)-565.3(H)0(O)19.4(/)0(H)20(O)]TJ T* [(mi)19.7(ce)18.7(.)-233.7(B)0(a)18.9(n)0(d)21.1(s)-231.2(1)21.1(4)-237.1(w)0(e)19.1(r)0(e)-222(e)0(x)19.9(c)0(i)19.7(s)0(e)20(d)]TJ 0 -1.0078 TD -.0233 Tc [(an)4.5(d)-283.4(i)-1.4(d)4.5(e)3.3(nt)4.3(i)4.7(ed)-277.7(by)-277.7(LC-MS)-283.3(c)3.3(har)4.5(-)]TJ 0 -1.0135 TD .0193 Tc [(acte)5.6(r)1(iz)5.6(ation)-465.4(b)1(ased)-465.4(on)-459.7(over-)]TJ T* 0 Tc [(a)-19.4(l)-18.4(l)-444.6(s)0(c)20.1(o)0(r)21(e)0(,)-408.6(i)0(n)20.9(c)0(l)19.7(u)0(d)15.3(i)0(n)20.9(g)-415.6(co)19.9(ve)19.9(ra)19.9(ge)]TJ T* -.016 Tc [(amount)-16(,)-343(u)-16(n)10.8(i).1(que)-363.7(pepti)-16(d)10.6(es,)-359.1(m)-.9(o-)]TJ 0 -1.0077 TD .0243 Tc [(lecul)-5.7(a)-.9(r)-909.6(w)-6.3(eight)-5.7(,)-912(a)-.9(nd)-915.3(iso-)]TJ 0 -1.0135 TD .0252 Tc [(electric)-529.8(p)1.2(oint.)-531(S)1.3(D)-5.4(S)1.3(-PA)-5.4(G).3(E,)]TJ T* .0243 Tc [(sodi)-5.7(um)-1049(do)-5.5(decyl)-1053.7(s).4(ul)-5.7(fate)]TJ T* [(poly)-5.4(acryl)-5.6(amide)-375.1(g)-5.4(e)-.8(l)-374.1(e)-.8(le)-6.6(ctro-)]TJ 0 -1.0077 TD [(phor)-5.6(esis)-5.4(.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm 0 Tc [(PK/PD)-340.1(OF)-331.2(ION-353382,)-332.4(A)-337.9(MODEL)-333.5(ASO:)-334.7(IN)-335.1(WT)-335.9(AND)-330.9(DKO)-337.5(MICE)-23255.2(233)]TJ ET endstream endobj 134 0 obj <>stream AdobedC       9 s!1AQa"q2B#R3b$r%C4Scs5D'6Tdt& EFVU(eufv7GWgw8HXhx)9IYiy*:JZjz?Mp[.[^:tk? q]bEނ2}Iu`\kGtɠmtsNJRJ>L|j2O7w:ETҧar77S1t YAQ9OͭF^);'ö+U[hl9<-}>{r*94P9[s\9W.?7n?+7n?+?~?~۟?yg?y?y?y/?~?~?~?~ps\9Qy~/s9o99ASw57sM9bo?y ,O'c^O?y?9~9|sso?y |[8XXT=/6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6E|19?{{ČcbրӰRo2%ޘ[rO JjG_nmBDeՉLE;m`hO(D:i ]yÈd07T"jDZw )Z# mn-ݐJ.K6^\w#.#ZN#›kڎkxmW<\Ny\|. zQͩVZ *1]ECHH ‰˧QV>X/^2=Oq'7~|]KFS=Cμs _pGh$d$nxS{7ڣPЏ,h ?5n=qsv1O)]\ J鮐݅'qQm.|ŚAJr42E{I$ϧŮU~[ҁHPhk o\ y(&u̅=b;mo-%Kdf??c{v樀t Kk3Q>yD m i Ӳ=I ,ipQGlQc閩줓 RkN͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳ`h_ V %}aJl^.#H#D]zM@ y*ܑ&pvkn4[u2E6vT+bpAV!z{bTAjeJar0HYj!tQQ\;b 4Rs X:m4wW"犋(;'lw lCRXc#fiz|.ƿ!Iy7 ӗ¾ɯDaUKK^I>ԮEuME+h5=JXtX",K3%#:C^qD|F<&bx*ܤJن}hnV;z6Č0d#af D'zqu#|$>|i%s7սf@XZ/qXۏ*q=_O=V[^'e֜C8o,OpDn-R0[,ty5~-F]q.b/#xrPZTއk8ڪ_AeWPx`'ⴓ !C*ןZSm[p, tss#?ǕW|uWR['ӯT;[h*Ej\6t錵4sX>YĻGLo]qlsC"xթ7Z r VP4fk^6)X$Xys.!)F3M"^f5ck17|RHjEA[[L8Xiq,p6X?7W1G"0\>@յ <+[\8P'+TWЖ`rpiB݉C[. >Qzo:lHG}-ďI'6csqko4d-iJЎo%jD.tX@9G*[+ARN,Ujqu1wEbWSVYmHyT,Op0`y ԑ:Gm owig 6z5_0HH[)]:ͤO/$2+*T`Z^e('SK`%%D\;Ӷ'|q^O}[yFHO8,ua |*6ܧ$L ԣ(&7l7Y hF^lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛!wIԮe^HKNq+ƑGv m[D&x1Q)b?QI)ώEu6>z!SN1Am,j:V"8M'MwfkuhG8ekj$F#R%UZ)1”eL"~xi1'LNX~-ְׯqhTJ"Y#*<:c/X`1)u#$F(GlrӶ8c41qqpYEQ8`~8MCY.iSӑFejI퉯ڌV+q:3ŀr;x#ii<8젂̷Hqs zqV1D{n`V%Ieb?rfypej\ʂbFY(/ОT~fcwqK Ƌoo$7/ zd˲SzZefZJΞBN5'~WZk1G7[ITv3(h K`=C+&WLhFP7"VZҸV]E4f{Wtsm~^?\Fo[_wO7ћV]E4f{Wtsm~^?\Fo[_wO7ћV]E4f{Wtsm~^?\Fo[_wO7ћV]E4f{Wtsm~^?\Fo[_wO7ћV]E4f{Wtsm~^?\Fo[_wO7ћV]E4f{Wtsm~^?\Fo[_wO7ћV]E4f{Wtsm~^?\Fo[_wO7ћV]E4f?_Wȹ挕i@ēT) !>kCLu-$*DJ`}f&ũ[I^.:#Z6uKg(6mb_zo5_͉}#%hp PæPB £mQol0c HԚ5-AZ{ +0pvi 'udX~2+_B4uMKLtum_! ZyoRh(V}mXFo}cYKrssG8bG_!~gT4M8᜻ξus)u)m죄tc^C`G t?;jYϭQXIpǘiZM"؟1)i&ڔq^RM\^J6x7|O|c|I4SKE> )W9|O[bpy?r`OMUmCm<+"0GmG#m1P=Cm<ED4ixՍhMj+@0ɵ޾ڀ;Fv*(iQ'╡|zXWl>m5 >RIo, s@Sڎ}+SQRXx ֿ4_[A)4Sµï&kc&_ k&ޞj::Z}rtHŸPhgdRsђ}/{T:}FA9*f{T7VΆ0uHW<^Z5h>}p%Ŕ*56R6'{N$bɂtjtKA ,c apyP~ߞoe|[K2"rZM[!k{+pv3Q9ʹ2Ѥ6!$f>4]j6i8D (C .u&VrJC%]oS7LOPT ]|kcyiH3CIM!ɓf&%/,\zUol-05AH#9G|IwfW©μ[ c򷛴0ZMq*eIaF GƥGL&WSӭiЅR7nM@kϔu-ef܄D*>mɦMYYnJzƟ%ĜQ䐒Nl|4Q*cRX׈pEm/?dhH)N8;i\M)-XJtxHT*"4tܒ~xPp TR7;U+\f͆reu!O2',m[XHmj;EHfipmVPq>g͛6lٳyW`$%R:BĒi&l)8+Q~C15떽=AlN)Uzs(PNT*E84޻f@-߅F 2:*Mƙ\1 1<FUCrqޢai RŹ erRH!\[gM?ㅦ,?mp~lʵE+_P~ɝ§$Uku:H/-(`AEMeJ=M*dO!V xU 0Y+CQ((_-Tbi3_F1t0"M"҄`it6"]i6 _E//q.h(z .5BEfG@SlƜD+,aqh\zf?Gȧ >#>N6OaayEZ>C-|ߠ5դX.h+  ^QLyɼu.sjldo՜_ySo6hwzyIߒ?$^{yu}w1(ětΛaOΥ5o,B; %޻k>IgNHJrS}N|900ECu6uk%@b w"?0%_Ŷ_OӉ~&?707_,lsËTAz)chpp=6dZ1 "gZijDv7;FʦO:jz`eTlMrQyXzlMȧOJ Cq#ҔژQ,vȇ?uԏ֏c?ㅦ,?mp~B:׷vhXdUrI2kp&ֳE|,VUb֦ӌ M )jᆏ‘=XoRqڴQI`JkyW<1H'%b_On4Iᅤ*L7_>g2q(Wu]/ZIuKֻhྟ*~/o2]Ms}>L"0z5c-S5*kש5k?-i6.6OpbU1N91ʻze* x=52LS-GLvƼ5R)8^zPb|pFlٳf͛8}_[zD >'ٓtI |2?./5HrPx:>5d0˼ NdXV 8M!JάIQCj"Pĩa) ʹ~0a`o M"> ԉT)H&k1i[\Y5 ML~cjHx$`N4!kAdʳ\ˏ-YV#R׭oVHZ5HaN@Hzw5]n7ͼ\I^JKMN7ʶSԶHMIR4٘g-+yYb k DT-iHaJV=NƼ)ʺ !?Lm֟hx،um@o /0[Ք_ô]N. R85OZuēmY@f|"S%zb/C@[ Gt=fP=,If4?dmr)L!G>Vܚԥb}E/xSm9Vt@9H@QK˹V(2JͰT$ &-@/edUpn[BY 6:V՘8(,8Cqˡ,uymCmZc8e헛1Njv˩ )xV|pFlٳf͛8ǝ7=> 0b^Gs-q`J2T+|Fbڐ#zl @ p,|%OAYdl\;9(b\ʸLmdZStNZaF֕cyjlP-F0>GLQKk5K稘~9Ӽo^Lh/rε-6䮠P-{\8a/2,]gD8 ^&6h*z`(i\蟯[9bJW;˗Im$8fxק"i+SSw]Gr+mR=>K]Ej7^K_J0 Hu!Wz{蚽k-ŕ\DEUVGPQdVߕkL4-s͈ZIβIةȏ_x2oqK:a?C"Ul~hgJ9 ݎz\ ":0;¬yp__{O2 smjx'~{ٳyAೡYb|q6T 4q%=%c`+mS;NeA4zwTNrU S |-I"rSL^6W3$+ y VSmka,"@|w.eFd9 o,cqU#ySM{ep5`?.5-WKb''-H)5 >kQӵՃDD5E@B>a ~pӭbf%b*PD@Vk$13{ ܶSL;a4˥sPeo^0ԮVSqzۃfqc1 \VQ͛6lٳgA ٧EX͋E;'1ZU}j0X (#E n'٬c˄Wr|iFy ACIYH?F? 4۟KnkM!WIAP"vGAC oXaB4-R14+kR@*PTwpI.ld5 ApwW׆9*7N]ǜʯe *k$Qq,$?;`ļE(:Sy`mQ^82G*cqP+0a_#i3Oߜ9Yɾ@?$֗x0>Ob!?~U]j" ;<8̿>' Dn@%B+HڬT$vu+ {,c @v~</ExKΡ) 5%*r%oj~˓mr^<35lE`3Pk;xgڒy&ƛ*>x~Um^ܳر'WF{qErk;V[Htwt6nJZj^|F5.qo|4Ѿ_.nG4,Sv8Zo&$rM=U{-K|w͂V=SS:6F֝ծn--i A!@?9AE Q?'̭J ؏:o,ts4I/3or"١FGtWHUv:+HBċ QQU@&^ݮ琞rč'#` 8 l]BQdS^p db87q9Tvk++q Z#ͺ5њy )ɒV/Q*Mv0dc]QVDUAd:LG'nQO2}kz1:Tt`FAN]N[A=GƏJ8PJm=yT P>XeTq 9"QELrc1hqAv@ۜbg"驏%\]3Ze$sQa7<{'fwc3}Z$zr ]^_'V-' 9Eȝ_50yKwR-O#AWmϓ%-2Х?o{iMܵ դԵ;SȒLl0lMĐ(-I{-6MPU1,: h/}cuȣMXV@@-rRۗX/]6p Erw``k8{;f:$^+君$Rxe,a9x[Zu='{"$B~nN5풽?A۰’ :X%A}KmA`B=."{%m-dӣR#~lѭo44vU "ӣoֹPyRǓSn512pG謳F)g>fI衏!WX,4Z{B{S>-~SAhu[V{W'Vi,kk@NG?1초PrEצv8Zo&HkpDV ʀ﾿kgl<FAJɃBG_vi?E&]#Yi#fS2eƜ?Kjv8ai DMpI;Q_BBNACl7Ga24!(ێ& c1oݑǾ:B]eaRBkZ{ ZDC_M͔1&qłezIPi @)?|q=gNRot)!5-Jp#\\Ǖ|2hWwWS!}}8%5yJH:$>`}4[!Ojg3#o??~\[Ro_C.qi?||+-Kvh":zޣp4-$..1sڥΡmf LA19"[k;TCV /uXG]MSF[.+"pj̿qկj}&B+icr5inӬUJN[կ[Hy?F%YR+V"ќ\kta,r7؃3kr bM@m7=穥,5H<-í*ђFE }8K}KIb~Z¼j ( g ;Yʑ#PHҼ$\Zt#Pߩ Sԏv7Z`iHOqNa?,-Y@(n[Ý&UޟAWVH^E8pALj$7QQhm2ʍ*LVkAi~Z{gQ'e46+KI/ƽ=L /$K#",1#la}|/s6?!~A#inu^N D*Eq1F<`do Y^{f]/:ƷL ٲ4ٲA*yVIRNMUU$7Xo0& ĈMJcpGQP;}#T+S=p%?RG*)yVF&UJQ:4pq\Xs"Y4j*:ëq\>K8ޥX-zjpJRgeFf@~KBQjhq;e5CPq}t l+RHS5k؋^t8ŭQ6i{%Wո5Y]\Z-z6EONFx1۶pi:}7[]U) TTr=y˿-_ՄiJOZy6E.oZ)>_}Gigi\%b5v0mӥ9 -:IEBME u]}Ɩ$#Hmѕ!']*X iktWM_zٷՓ0ʳS.o,Zj #F%guifGdLEԐT=rWuAo]K+ˍvDh|>ngQWǤk"t$ޠjq:wk7qIh1(_D4o- 3APbbiNz~\N1GG@? ;卽%Kr5@ya]ōJ|$P.-Z uӮɫtpܚwXsiOȯF܍^A@ҧw@E;gL]kElRKiBljÛ)E1D_u-8Zo&͜+ `VW:|KĎ9G(e6VVlk#cLb36]6WLMҽs<"(+/%5%<>E}Z/ӾfЍp<POv$uR$|Z)jG\WlW1{WeQCChNŤ>LhEPz>M28ųK <`%91EGQT_iMWQ3"+OftEpi4Fal  6R a#垕HƬЊc̄\$ ()g͛6lٳg UoqȶE}o:ԁ?Z4as-yR xҢ~D~ ʎk`]RX$ 8MqmDc._kjy T&'"sllȭZut0R-qujPnVڅHRO:ƤJ-A,rN0v~>~G4X"1C~YHaMa+PvYew.(WLeMl.8" h:T*(=q@OlpM͛8WJ: ӗ^hࢸ3SٳeSL˦U+( Į-axH"-H̫ޘŹ.5K;hTxWS%Rv#lzVjc^V_,ܲ;PeLNݭKwxeP~`,TkkX7"ĀM)Q$rWڄS4u` #K P8Z'SICm]JJp>ۛku33L+_+Qeu~c' |߷[6lٳf͜/>?SA?P,CQڍ^FpABhV+_ڻXmn7*FOs_c6'K&GqLb #GR|?/>\m.1:gHAjD*ӝ~5'ԷJVR(w&K](i@@n}5'gC=Ɉ+oK$wqB9|]+im}V/-96Ih5RE!&2C.0ѥnXL򖇮"%f,xl~v~׾F^.v.l${i*[cC='@E{d&NiAY/21[iD\.-(W|-b9aE"jgAQŕOp]S!L6Ι MXٳXBijNckSQF+eӾ1A53S*Dn7*ـeq5:jP+am*ToՂFF&?zmUTr6a1DVyE0a\jDj\TeW6^XjPKȓ09 ܗ^- ] ]A,+P58t M[Qm>%mYʂÒQj* ONa]Eu ]\}4;`dFT_k #; PhH?qlٳf͛6p+anHyy6y o{&@bv m'vwU@<ǣ+HŨ{kU6 Ob2R|\s UUGiҸ ]9$TGlUW`Ƹo't)EP0J1և|,wL,6@?̘| u?<0ֿ: f8˟w,c^|93K\lS|]5aUoW`Yp˚W( STկoyLO5 ~9.| YU1TL ^jfƏ6b|2rǦP^tle)X9te+SM.e˦VleQRh2TkF j7VDt뻰5Lx75SIHV2,-8d+KuśZZk]zDQCZpzV@C}SP~DfXa1pvEjqhgoG8lٳf͛<*2Vu86/^8E\)Q~8gQH؍ڄ yFpQcCLZG 60X^-%@Wф7Wt$F3oUUGdN:uzK+0D<_ryރf|F΁^)$cBj:a^WޡVUX|mGzS|Y<ݯjmJ$.ěUdڪVc5J[+*J0.~TJhOY/ȩVX7i~\pTZggT&K8L1x˜)ژOQب_Q6-J z#0q'Ζm+@0ɵgbW?YοXT%[r!Ѫ0(Ot`qܼ2erDƁV\l1F -Ndh'Z)=OJI,36C͊Co)F21yɧ[j˦ kRCGWuBY`M[Q;fWNSo7ͭM:k3E+0nc8Lwǂfb@`Ďˮ7tj+{@^Y9/|팖c#;cEaQ.xsudXZ;r4wVUAˡlL~c-k/ƯFUD.jĊ׉1iOKP@rPp=M,3#}*/_6lٳf͜7.?qq ,`?jאwlVGkY"I'[n]:~4)t1/G*31OVFYY PUʻxw I98TH?4%.1sMM7`F"z!cR<3~vM]j|zknFHAu'9|!NEĀD!TqMiCHXmH4鿾B]jeB яZLh~LѼ:jjxЊ*N| ̲z\#imI v4;\O>iU-zM9t egEPcޣBS$уQZ0ſ(j' Vq۾ti \6p5C/53 $cL#{W^2D<Kxx:}JaC ErT1T]j؍&5$*S\z צY'm)?SZ J^"r7.ۉ4$=2()ř<*r4qpALh_4T1 >9fAt4Qҝ`|iv jrpVԙ V’K4.X%, *v +;(w󤬈X^C_R͛6lٳy1'Mɹ2H؅ՄXx| YAv)1Ф@ ӽ1YǷUbj)Y<)A-Sl!CZdjO,9V]STtKT 6Ҽh2*R#v]{_|m]ZY?MnI..4-Dr/ֻ὇ete{Pn@>}G'8Q#j=9ʼ?(WG~u#q2g}mǑe@ 6|D!o5K6)N9`ͽFYIJt]$2n E V2}\icE}HJf6;!_gJ?ㅦ,?mp~lWSzY6_g`q ~">'VDmJB +'52Yyqk/6jee='ĄI: d7 r0dWG &#I1Hx 汖yP efJV,w_oDq#m#yFI]H$-EL cVCjzUj`u*H9".EW"Ipz%r‹5qJpWnuZ#*!$? p$qn} }N%\ *٪xƙi} 躤7t( d) HH:0d` 5e͛6r2!&vDc&vP UKq`2aacaJxʝBjlQ2A툯l_vj4nj$V&Y)2+^DZrkC2ѻ0xƝFy_ԦĠ'Ewqq5ϙ  @|!oZFdfߦt5մ03,뺓є#]MPѯf]1 IJL%uɇ3G,v5o]~mX5&(pq֫\I4"RKfOBH P,EEr]C1@5aէ@1cyk?-^Y.r5+Z/I HGީPUHï*hC-4q$it29,p2e]d#Ζ^bh6?#ZhfkyIh!cgT)2zjQEl o'c\,bWR4p;/@O>Y_Fe;W%qG#9naiJMc]Aݤ솇RT`?hzW9?v Xj,yڸ#)=yFSi$gZa5O\Y޸ Mr;{1oSƼ@蚤s"`A Ph1tj7 ?Y&xXQu {4?KqexƳ$3?1 }XI(Bҝ047~tmn_T-m! wҹFm0v;r)lG&6G% =6l>di0CMɒb7mdkކ^bC_SF66Ɛ8n!B $^1K>X Ȟl7-|5=g&W0SANtjm<{-VX#vȨe?*~ZHJg2s=-X_z{iI lJ`6"YBevc"1Gy:s OQ icP ]krY)9 ę8G7U$nrb5q2+2?L6Ε MX)o)ymy'I3R>{ayQ{Cј|09)ӈjkݷdHR8Ei7N)Z1nFUUGlf$PrE08610Ĩփ+^A@)|T4l ((;㔪5sTxZ(20)3(rSj( Rt=q#r<êGkm͚8g歮xahIoY5܆;iDV"yӿ':V9Q.戴?"etK˥zpKٮ;P/zGL9ҵ+VNK%ҼP' !&ɑFJbRB ~U#'cʆ4n@ݔKSkáu)$`rU?N)EӦ{^M]2-TI*$k"ԓ8N?7,IuKAv[zBg8Yh^O0ynAF?x06߮-v-o^'ߣ~*o=y>mk>VHb1?LV'nG|""`[;\Tb!rZw {f iĎ4=6L>@}OC80Ҵi \6yWA*JGBI lv%9TYtj4F:} <ͭgg ;Pmpfu hvVcT>4ݖn-LNڴ~2Jف1Ws'caoŕ~o?}f1l7֛qϘ{yfk"$iwT8NFVXDjFPifu-[^\KO;}~uk$:j:7o1i鉿thAbiۊ^+1 5< Ӛ~WÃLB_4hзn (t(.J'XؐY(6e=N`^ҟo04f_Tn>6A-S`94?( }.9|I gW\=|r~k'V*W\OTSe [/TSm [)%uo6]{b~G^>i|8+u'V/u'V*_^f/uIULk7]l5W}{믺O\GjPn|<JQѥ#:kK kN\EΔ Z{͛?QA-8h#S~V~r@ka]ֻ.t9C0o+_h9W Ɩ@J~t*#:oe]bJql?ROI#6?#ʇë?{{\ _|!6~f<nOU=?m~7G6\o8$>y bB)y+p%h=U0HS?p҆!\?Q iFSnspoQ7xf6;Pӿ(`S\/sqO1Y=Z/sqqޛx6797a1FLspo1MiLxC4el/60~f͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf P]j  <3q<3Pxf7|n+25f _Yyt;khiޕ⑩f4>h. xhE6UaP~}5b6)ʰl,h0 iq\Jo)ktln8Պ⠞t=0u_zp&)TVn#z3y~R+،Mdѥ{jʠ0iu{E$Rz7U 'Xw{ȭ5;m<a2?JM_;yU5FX>/^y} J|<<3PxfAᚃ7ᚃ5j <3PxfA5j <3Pf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳfiO}\eUAv b3|-0_R[El# DɽJ=p~*w^J:Q nxVYf͛95+4wVy+9,pFT({-c0mdmɽjsN^v?U5<<i,w i/2 z*6" W6 obaJ/˵jZm?HYƛ'I-/zOJi63I&Qƪ(~Fy7nmȪEy|O< }Z*wUv2u0ɪISnr1xQw't[O^cb-H+Ҁ퇙f͛6lٳfͅߘ4] n{쭝4S@\G+ix&i 4/t8Q̈́wm0/ew%Х9:̷J`)xXn_SoG;=/'7Kv9z_ #NosoG;=/'7Kv9z_ #NosoG;=/'7Kv9z_ #NosoG;=/'7Kv9z_ #NosoG;=/{V?y/K+i-X䌢LygH⸳mJ#Qb['y.kٮoa7$?V$Qx|ihq A5Ĵ͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6S"v *M'5 KGT͛6lٰI6IܝWm/YCiοKuo_s~6,\ߡg_:?7m/YCiοKuo_s~6,\ߡg_:?7m/YCiοKuo_s~6,\ߡg_:?7m/YCiοKuo_s~6,\ߡg_:?7m/YCiοKuo_s~6,\ߡg_`q(Dcf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳfͅhҦiP5,e4ނ!l-UM9FWi#g4"9e0FfR->?(y>5C%LGQ T%cMvѬY>ɜ9L;ׯ.w)znCA~a~te" bW@"7ﬤ?+NG-+Ο-#IS}Ք0'%'SWKoOSVKoOJo2s2Ko)?_}_o3~տv|7}[o3~տv|7}[o3~տv|+Lj)?oeտv|7}[o3_V?OWVKO|7][-?Wm_o2Jjm2Ƨ?oz[LSef%%'OWKoO|7-X~͵{ 1P?cff}Ljm3}oWbW=?_5 oO|7x[}L}`W涥QEJȭr|[^&~\#lR"UEnX7B06lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l/O& Qn֖񺊲-?GM>mp7Ȏ85x##N5n d\բ eQBG>ؔwi`n~WZGE{(jk4[ʗv\IXm"1#4>8|IT/)ϥm:?]]!U24[giJϚbC}Zz9q!jQcօ E2 A2Ǚ뱂78f# PkzNq u9NhvG/֓ސI y #[2WB~!O1NVreƕ/<զM奥uO&ZjVcV2%ҔCŚGme©t[JP\dea33h+!lN\I5h U$s/<ւMOMG* 4-MT]]'yG8aPDP5-`/Dx]2Ɵd/("}RQe?y6--/Au5hBLA𢓂ΞVe五."G7ss}MJ>XX,gdbށd#jdvfkn[̶H*>@cH[NgnT+&g<|%Ob0%M?vqۉMd)gl>I}6jIƓבkҴ1IӈB%7ti6>$ E|ޢh0D~[#^+hpF ׶-M}bSyHy-c$t4kI}͢MwW@UV4Oil@5b*kؚԑid]~ѡ:&+}`uj:jKk9t1$ Ks!6$1lwʗ/wΛdlyhӄљVsiFm`y@ʇ S[OE-p @,ed %H?Sl1=_WR+ʼE*1hZw$҄Im<+& ߈Ky+/xJq'!"QBEװɌzKX?2˚$@G^UА6qLk0hP *ø96^QČ~u?M,HOY Pt,ٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lNSJ% a]It!{k/RN+4IGÈb^8isǪy.ƷS*6; iЕNAbOu#YZى.T 8 0AZ훈nZ x ăp&BӦrWp6̏@PzPo SJ4(5+T"45%V J=w];bI2z1&;uV7Rɪ_Hp><o1ccڴ;GP+ԁx.QEi:qp̲Zv+P@q\XZ̤Iuz\Aes xY$EpO KV 1_Sl ۫B#Vb^ 򇒼u ctW3lcP mLNɯfbz({30oV%8V1|i bxgOz%b1Vr\φAft]BUqsm^gxBzW6jPr_.&MR+y5(jڀ+o<ݤ7o][Nq V FF֞O*d %h'CvUMV0}a>דٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lF(e)l[H(]7KkUCݜ7Hm-,Þ}%n.l-oN 6^])07w:%,+aYEkeҤoLSNLR"ى Ă|LkL+\ޒX(p>5Է|Q5[sUnj|Jp]Gڣ3^SWE}bF |1i#}V" -KҝF0!a01VYh3Zji]ž2 |/u]?0Q΋XMmA3s8$oUQc-(CkC!lP޲Twtujk8icW6卽@N4S4sjX:5\Gf2G%քV"[嗕tKm5QF 7/]߁܎lN/)j"7JZ \8FnƢ8cwb$OQGy`uPI㠥_>AwѽIފ0*CrAm>ŧ]j~Oasoz7\$C]{fYvڏ5cq$Z}fH.?ݤ/և;ɖw{%pIoO@1)&>*Щ5og֬2 e3"z5y%j8PKk;m5lBNZ|K_l>k~)Gm_}6vʑ$hb΍"-i䒶;A{׉0oVPoPP e{ザF.5cQӮG{z773G0U 54=>G􄚞+^[\4_H@7*æMHH*@ *RNVczBFPCWlr(r1֧_۫|A + F~?ؙnqUMzȯļ}*k,ي|^&Iem^YV2쒎2)jT;+~V~_}B+^V^ !yb7:I,,5M_J`k;ϬHeB>];`|[^+(}6$vE*B b@%S̍[Qu++{[-ɠdU/y#E[H~aj sƠbѧTu_.Ń`1O?P)C7̟s 2\T3yq?P WO[ˏ9o_?o.?~e弸f_o.??o__o.??o__o.?~~e弸Q~)_̿wWC7̿w?WC7̿w?WC+W_[+WW[ˏ+W_[+WW[+WW[+WW[+~dS z~^\T12\ ?2\ 3?\\ 3?\ Nr  ..?/Ϊ6gPs򅮿5=ʆ!J*iᒬF𨴛<_0E]7NoZ+ m>t-UHB[p?k$ڭmc[g2GF9.hV_YǼ G֣`MGɚQnťh=6Ώ8 E2T\1e<#W0:o9G9RDHP\=#>)ruo0Kzz.HFM0A0"u4QSL5gI_Q5=mN-~;>kKhb2Ί0QTg8a axjHiATLXr^˫Ł!jS|7ra^X(πav8IiMuda^7XƐW\~Qye w +'w!V:zݍЎ ZOW7c <戮-/Lu(o"3)Vf#e3N[hbp")$n@ RxAZTNY;{eTPeBI!Y*?ƪLzB5$aud%iH}Nr)Z0tL39TM/!O# u;c9Y&2H7!m,07(5>DaZH##dǾ8n{T{+m: 8<uOEFZ㐛3kRi}%xr"EyV3Muʐ!;|ztѥsOƤG_P*|#!%3WOヽ9S.1'VNdT7lx7Lz2ʱz9aMzޤN$hjt2H}EB5#zޕ` ^̲kPV"S,@:oG7-So Z{4i~Oޠ6lٳf¿5-l័Vm/st up%՝Y`!۟28}鉵ga]mfh+75.KOCV8271 A mrznyBD-Ȏ \io<KVm3N:tӖto?*s{A4S*'ycEW|amiݾK}.Z}\cMj*8>xgvާ TDž1)޸{o LriǕqޱ:b/\ql!ĵGu&[oOk>ӱk+I.[[K4TAV;{`O3hwpAs[DJ}n?71O0RYdm|cosm^ {~[,W=A6BOʎ=)Xu@5u[ }>rh۸FCl{.t-N*W?Gvzt6h#1ܒ{UӍZM:v8Əc2l;4j#۷!S9-bm:F:m)ue1KR"Rެ`1O(#P~8S~ eNG)q E/ TSA~`2Yi*! IP q݉g7±ҵ\~@81O>pFzWOy涎gU2b+ˀyT֗lٳfͅ~k[X2ÿ Y`ttF#s)H]M%)(MOĽr"\8F:eHA5"`þ,Tצ>˓Hb_EXo3yZ @xYlA1@`EŸ+]SS )4?<[_3WAAm$OfsR>ws^y'EY-cO_q{L]r&k׶"W&Z|4kޘW˨&f r_lzjuw{gJ¬P@f[n--0{Xչqr?)SX)jxҹ踕rzpB)?V9ug]ɖ75lؕݺnƋ22Ej##zU7Nލ\B쾙e⪴<QE/0RYdGT|ɤ[ZI#Dkk"~#VUΝxi,czr|3:{[k76΄ 53X Z @61+և"^zдUl帗bP>* Z"wɥ1 mI2Њ}cƣsO0dlq6S=5G5]MQs)۸.Eی$lk9\I<Gwl;oYbbƉmfW[֙|ӉvLF9GR :j'n>1,-)B:$>^?S6˱ZBzdMY90b1?.h z s$l00eqRG(,ֹ<Nz,yE4ʴ͖ɨ;oI݁:TZR)fPv㳍,4QHبNӮNV#F)"#A<5rF?*qx~5ۿ"89~GedmѶx]ֆ'?Қ9s?0_)gu ޟgld:^iwi BB~iP7)Y\9\A=zo\-.¯6wNt .kk?(pN[Y1)mB5O@E j]a0FFǪ8MI:G}2q%>gN,qF#@YݍrIvsq:zƒ+3c|KafmZ#@G26.!uq>[d/z̖wVq!,A8KeuZS\Yh>jvƾNfS} n&3r\Erച}ZTjp-̜QzSRcIbDuǘ[g)N H)c[<]^q=FC?) 9Y S݉We-$іq qj+@KvMb9Pnx 3,n䴺9qhPG8O}~w۬Vȍ7&mЏ]bIGLtz!w5 9DYnraML0>4jٶ8Gs+C142؇J}73\Ν][K ?#*+đJң68tVMA%)S$7cSIkKafmMZSXm*Ă[f4Y߱I 6WaA_fpNiDU5N&yS|(ִo&\ؐ#eA 5ZEp5feV̽85x 巿3"+uxW%wޢ琝Dkr6ۈقxژ+UXjk;sQ"գIb9~!#+͉ΉgyZ彴-}6Wܲ|iV󦭤m>MkyDe,w(3:|ߣ5PTҽr`dl-[KS.%*;G2paԞQMSS_E魙nr41ƠwrIzKIỻc;"#H(N =Z<7Y߆DF@GҬh~x.>%~e~:SH7FؠǏ|212Teæ']늕ז*S?<+^IdD/i"QMD'Yf͛6Qmc`ng'5{[O%qoi ^eJlZnr0N5H{➄np1kn?;W@: 4xx #G*OlmBtŔHx|F9.+K=Hi߲G l[Y[30w?)fcY0_5©M՗[iW[~i=YGCՏOm{tYaІVSЂ1n#yG'շ_eJ}73\Ν68& !??#_i'ZVExة^ئ;xF?/hRh ^f'++@8ǍNvCf\s**1-*lUq!XAe삣t ;5XL}a}WS@4qw*a7Kl%e#Ujw~LX#I&]B̩ˍ|k}'Cﯛ@ѧ?Y  $e]YhbxlO p1ߋ4/&jqk\K}++]O-,"J Na^tǀ)fnA'.7lPtr|(ZJIPr%|G3"*s6lٳa_?Ly˶:I' 3D$XYԲ!? NDjlsDgN͛ Kafm)_aԜPƑ^$pJx#pFM6WLχ\WzΝ-Ŵ+)Z)VJt83ۺZ 0im`~4olȨ,(Hƿ< =osPupA#z6ڢ}vIܜG̚" b7pnY҅F K銉ڨX7I86AS@ޔfKG4(*ו|zm_3y+w^GŸ&)pVv֣7Ԯ^QɯF\Yc~mhO赫ysR81%K{㹀}1LNQ% F.g;R =h 7P 7yod/c[1][v9絽ӧg5Scۦ,?9tabiBJ t.Sk%~J@?dO:y_Ǣi2Cjm63ME:Zc՘'$_m¨,({vŸ;FG'u?K`of;6l/p5?M@5Sfunp/ر)B:%Z mMeS(1⒜5:TV]KeK;uGRpep[ޅzƟjUdtqFS^XM"D4[*zR ^ͺ/mUy^io`H}e7nK=ŢMr}FamM7q'0pJw-#"`GcdJ{]zh}Lz<#c]U$OhyC݋Qxf+(F8nj$kyuXDXk9 -'εn kR h\kH"v]y93~VJ+t%Œfe8₥q'8܃8 DZ6Q@K󦿨G+@Hʼ5GbSU#~lMѫrU̾ZX˟UG\ꗶB  BUy&T*Ew/|e@е*sͥ[(^(T5 dv!-"jq%>gNL}A3D8]+SEf*s_-ygZլ"[?Bd%Vv/0RYg-o4\yOUZVto`*[k[[iRhut vǶ7C!Fطl'+liQ#*bGFT,>!'|~lRx kgkyg $ 7]m&aON舁sprf+S]M.-T!$?"oSJt\EulȄ{20Jm*rN77.a/fKhy!դ {T_|iKcmdF8$H'|Zi,тD3:HF)J6' +o N2({bҙcƞ_lhUfJ0TvIL~Wmw Rj:ro8Tƍߴ^%,-cU JUCI]9g儿aIc꽇$~\J?k 8~a`yUǒ$дM _LI,+Nխo˩c^9aFz4VԷX'u@ڿN!ŞjRP0 wPQsi+aU/Nq>dqs˂>>|rT#ӿ0l3Li~e@-]K qSk4>>}BYWr7DQAW6/"`ΐEr=Mij Wc\0Օljx-Y?qQ@dP0.v~0!-PǮyA"Ul{l UAʷa((b qN_N5bJN,8z֍e+DqK0)n]eK MSΧ)8'Kͺ]\ WPe{xơ#%5!tE0$!S9XPر0835(NoUEzDu~V?ކ{x6t\7/4_;~ryU^XQyDTP`-yCM䞛5YiŬ෎(PtTKGs+WKH_>%PBdNfs%A_J('}ͺK61 I;n*}T+үz׷͸R5)z6pɚݟt衫qʰ]m*$51G}H`WTg@t[X)tȬ/xq<\4'Wv\7z`%,nv$5s^]4\xDrWn?0`ft>=A'ў<[D@GbI4:-+;D hFh3$04"+P?z0>-Ң/fUc$Sh\ѥ#|H퐏*_Ǽ@L|P( o,[NCr|l2ؗJ}73\Ν(1FJ#~D7vȏ,⚥ߵՖ/ CIYJGd?Կo6}=aTr1O'8(Y4"b"r4c2iBG,('T.@5=YPN,.*Q{Ez!W9yKfU }6$I^W$k.w-Ͱ-"MGFkƼXnN'YS̪Q,*1FFRuW74il &HՑjE0/HƫqjR 7"@aN"-KZvZ2/WVC%۽G i/s^+ZJUaȞbWiaہKc0yHqjO &/. wB(\iZ~=CKCak HXjĞ9&m2;pAk4/(_d^Ev SEmhql^Rv5%v@ywCvZZi,OP 93X!1pb0TLB+[8>-ݔuqv#RZWWҴ}eJuԛMa[[PjiL+tmm=tۭ1nlN&2 g꺜vmpZD;-zgqA^,k ޑ2=\AL&};V-^ajKnZӳf0RY`B* ƕQ: \̶5~#iVFu${್8nDⱩƓY6S(Twc\ۮۦn[Z$ioQC~E.Σۘl%4F_n9Mo;V>Q\. Q4 -$ x($cB U$nr©b!2(aNg#GQC&ԭ#(W`?x_mpo*J-ֺ{Ę9PQ4k(]bQc=(egg?2*U`еh= _aLfƘj-]jn-[gF͛6lٰks&[g"tƒ#QYZA$tJ8_hY

Qn5cZCrzRsľP* _4Le$fXfM1h]ADž^]2.3P-43AHۖn>$I 즘B>q5 x%"' $4_l$;9.PwS=Rv8anū85إx t4]oEoS:xDdZʽ)+0p]Zd/>( S\Z0bHn`Oof;6l/p5/MjB;i Poq)*4W?1Ɛ ƐHCf$}6`ȩ#3;C+JpAFEZCe&+ۨ}]%!> -1 죙`TCPKFZ>& 닪0EPkNQ1E`hF/|ieLj 2aU;;]ȫ~^hVz]2yr OQ`~PGf>u?6i,D`KӁɎFyQƆbYSOSΡXpcH({6]rj']Lc`qJ12J_? LͫԵ=:6lٳfͅ~k[X2>UX 0B~D [GcsE~GO$l^?:})qB@?x-/qK%OT0㿽+Ol%0uVlpE"EEQE `( cWd*+(w5\kH#늽ČT<P}ǔn L1鏖rvVNn5&^y*h5!V^_>#bگ^gN͛ Kagm- $~?#c<7LMqQ7|ԧ\a~I-ճ,2RZF̧b0]WQZ^Qf ij {)w ^W-4;xmaXA(eQcIJ-Uq^,iN@u閤p͕n;PaZw56Ưֳnil:+[yNF.d/'HV.P2&h:a󗘴6msG}P^^hJG)y$-x̺6Mb\-~^q1Ӧ5&F&zNظʠY?Ή6lٳa_?Lxz͖+-DC*Fk3LO;j cFElIW96q/9FYjo5 qYS{F`-;ONe`A~+uI)P(C8Jmˡ,P"?hwr*U/5euX"\*ʶ~ʴ덟hyKIvf=B2DEZmI&U#*CeVW)m 2dzI?!u9o&t,ٳf͛ (07?e>D2OT3)@+GՓ[ȶÄPkZ0Nod0uIEiBh;`T/+I|/CJvη+W֕e4i vB 0|9Xա}so7@^8+VFv4VE~aoi*Iy$3BʿXr[v7K 6Kӊ>=q $Lc;EQ2ē0Hƾ,g׭٢w!xT! (yD+}B{K;+Q>7ߘ-y$IVڕrOܾXW&ʒFFC2TFیqva#WKiCW*kd;u|-&t<ٳf͛ (07?eϟjEIMsdK,`1-,~'z q/Ƙ9|/QYMAç*P_yʖZޝ=&B7{Rْ\_YUcBJP=Iæ[ bp?NV,0ba܂hH풫MP m/dA5$Cz:Uηyd~~jk*sB4ܺz{N,5 F;QXN Q#ƇXC j8M8ҵ~o,^`vMPbێo0eq%>gN͛ KafmVƟ;c i|d%}x%zCIƼ|eq!i_, u5+ٱ_Y_=brME|^IpfEK_d`V4s7_+Kļ|I[AE{4 0'%V@A}b]Ҭ.gX\VSP Xt'˨\L jZV5 T(x"fc@0.qcӭIas$5; %pFLkE:IYoXAh܊lua=qAA=AF2K! HkҸȎ*)S(ywyCLs5n˺Na°Ār#9I86fFDYaqG`APsEf|8lO-yf؟n נl|i,횘zq_G!ys)Jw?z\pW+(3.X?>fɖof;6l/p5?Mn{Hلh{`}8 bd툮ylk764i2{EK,b*V] d42IHx"l(x>!P)6$:,qXMA$ x<}en|y*#+ 텺W{KY[O䶵ADEH#s\ׁ$Ӑ.;+X1Ҁ R8,D ~q”G ouzV*\?,}IڽSPT|0I󆫨E_Gooe#1FW }\ NHmR)$>+P}#F$1H Z4 +)MgaC$r}eↂl šZ֕=a V5~$S95/^y[R[{WQ;o,g %F['n"t&v^_WEw0L]cQEA"p Trsf͛ (07?e<ek3!qnҡTƔ@$PEkZc%0jFn1nc$E.q+L 78ׅPRK(Gb^[! \r=$_[iޝ,6=E$tQN?ok_+E^OC$J:w?t"{W6l~xG/AƵ'iʽa2뚞83S(/w&[ SOtlR'pʩ!bh+ArKYcHL(?X060RYaCYΐsfi'=}f2ޝeL3VVPi[sVC^qu5\h7&+7*o,]æ{۹+-=J(ʲFO*XmVORJE'aQGS%̀/n٨+͔M;eS7eULӾ'H~gn#p,ފ3|/o09q+^lT):fP5Cu<2+)V 2b~_zkg$[ڵ{-0K+[+d8UGqۦͣZxe Xɍy0>XW[Q )X5j0mհ^hq|P(^L~ݸ87bpO9TO|9Vp<t?@įpADk5Jۃ0D򷙣jBI[ḅ9b*IO^tbԹЏG3qHU1ZSg5pn<35䌷6O8});PPnrS^fe7r}wYRF ͅ~k[X2-ˏ:h]$- d1G'qOjTҾِ .FH#>Qp1i (w̪iC2xm̰&5Ǚj z}9ݤP<.& ִƛqҎ:>斔Ӽ҇CagJut~8c~iyOj)}9;kO}8]-[|3!DQY1A10sQA֋ n<nX#( v9@ӱƒH9#W_E,:|Mgc3A >%A80RYb4 ]|=#H׊ lw;N(D%IRShԝ؊r;{W( :A| i^Q j2Z>fR2P ?1 R^Wjl>#iTbǮ=T[}i)&Ӷb7Ÿ1V҉ I0Dewtj ױ#>dK~ iOip7 HvR{:B?Fv \C(9Mq\ Pvp_MЯ4a`\c-n #sH~%8)B|p-j_ 8X%r=G`hiQh#Wzlf[U52Im@cz;q,z?O6tlٲU…NmoP}M4+FK["ShQ 4*+sz:b9,uO-H$PR0/(.ZQ:ct̝\muۛ!]EdQ+hVrL_3KRդH䣩H0AqL7R[$ r=k#0;xcT5=idYaYi;EO.$mNؤBHQ HntY^x,<>OZL ў2O|giqޙN8&rm)M=0Ͷ >*x,GݍCJuƐCSޙ{AFw&[ SOtٰ?Կo6֢NDb) ٝ:RuІ݆pkk YTH'.HA;`+r7!D¹{=wˠTtj*^SaBqAcx-:or@;cx2 kJ12EQ!%ڎM|.G|)fޢRr o1afOݞjW|ݘ YN~9~ɧ%~떚nU=jP ܏zzW\(YP0Es~rHb.O4qK?Cއ;WDrE_G!k܀u,ٳf͈_])$"Ȍ=Ձ!uЎ=F-$kqڕk9MiAĎ?BЬ?GjW2c2~(I!+_C7?-~VAkP*rK_W/-~ O>oT31Ζ{ W9MO-kUgN{ U:ZT2VAkP[9kkP*rK_&?)?Crr {)*r[__Om~WBkP󐃧m~V;ZT3ʱU7Nֿ{ !vfa9SC7o~XCkPa9 SC/U7Nֿ{ !vfe9SCVZO,w:gGu'y&A&{y&vF2$0~l_-tME,<pIf#JD;(Z`S&RڽxjN].tX!BA 3OcHb~_FЬP9gE~i+H5Yk4KiR>hz2DߜVo O(_C :/Տ["?ۗ9ko~u9"2VCíkw:Y{6 ?B`w۩?.jVq j½MǞ4f-怋I\{yIXoҦ9vx.=juk`WNqm3}_3yKai<ϤҾt^9_R9<Ƅ+qĤV:y4͚A;r=5$rϙұr8G)O]i:`E$r-ySHlEhܧ:(*)J8c[i!WVMHAޠ0yZ ?_o<{qbi7|M R8W'?K.$?(e?1|ݒ0?\|塞>?w'ӁZ TzI47Poɿ.!OF?=srLCіsUEhfIBs+;wmޕhď5Q-dGJ1<cSF?д:}ȎI X$#:7ޯ.l* )Vٷ:lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6l]_G5_M7ڗ,R;nYs@tn&EnKƹ%!@Ș?ܭ!52 F $%R>0vzsz0"qi6Z|[kKjN>Qn$޽*9oL 0{+#qj^d4U:?{9OœRN+)<Ės @j 5cʱH#mbC嶻)bj`W|B-E^%vo_m'鍳C8fC'.2ߓ8w,nQ=0-F֫ed?DZ`)cWAH o,8u>&4?b_) ?A*Y)m._ _yM#L%}Oa0Nqq͢א/څ޾6}_]k]n849gGo<5Ծ /Iby r&f͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͉]Euk5FJ. q$jOG HNQ'7Ԣ8}N?Nos}Fߣ9G|>'7|NoC|Noq8mNp%JUOP>')-K;qQb@Z rNK|OĤm.;6{[5^Mp]}0>9|sP ^lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6lٳf͛6ly72-ݼq_hPDChX7W~AqXMOzGמHT[ucAq[{tOg5$Q+p"|}% Hnc$K8h i&v{Ҙg-K?!3_NSX{G{@3Ҟ 44M>Kg5Sʮqήz|R(0nK?[S(/L2N{ DZ/Ǧx?1ti`rwwZJ*IHӯi2kmݫkZPY!P9sWvȶ4&yqG.`$今8R3=ՉbV;/tŴ6{Uldt}gT]MtS+iaFVhыT|]?ӚEa>[?5܋y`y֟<tWJ;Ov@#{aH#USc'HuO8iRɦ!ӕ CC$F v%9>stream /GS1 gs BT /F3 1 Tf 9.843 0 0 9.843 62.022 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(addition,)-296(it)-290.4(was)-293.1(shown)-294.2(that)-293.8(both)-286.8(wild-type)-294.5(and)-292.4(homozygous)]TJ 0 -1.1174 TD [(mice)-635.9(exhibited)-634.7(no)-630(signicant)-635.4(PK)-630.7(differences)-638.7(following)]TJ 0 -1.1116 TD [(single-dose)-405.9(ASO)-396.5(administration,)-403(yet)-402(the)-402(homozygous)-399.1(sub-)]TJ T* [(type)-236.1(exhibited)-243(twofold)-233.4(enhanced)-243.9(pharmacological)-242.8(activity)-236.3(in)]TJ T* [(the)-252.3(liver.)-252.2(IHC)-252.8(staining)-252.1(in)-255.8(mouse)-249.6(liver)-254.6(revealed)-255.5(less)-253(profound)]TJ 0 -1.1174 TD [(nonparenchymal)-384.3(kupffer)-383.2(cell)-381.4(uptake)-383.4(for)-377.6(homozygous)-387.6(mice)]TJ 0 -1.1116 TD .0125 Tc [(wi)5.5(th)-288.1(min)5.6(o)-.1(r)-288.1(q)-.1(u)5.6(a)-1.3(l)5.5(itati)5.5(ve)-289.3(d)5.6(i)-.2(ff)5.7(er)5.7(ences)-287.9(i)5.5(n)-288.1(A)-1(S)5.8(O)-289(dis)5.8(t)-.2(ri)5.5(bu)5.6(ti)5.5(on.)-284.7(No)]TJ T* .0119 Tc [(majo)5(r)-519.1(p)5(ro)5(tei)4.9(n)-519.1(b)5(i)-.8(n)5(d)-.7(in)5(g)-519.1(d)5(if)5.1(fer)5.1(e)-1.9(n)5(c)-1.9(es)-518.9(b)5(e)-1.9(tween)-519.1(g)5(ro)5(ups)-513.1(were)]TJ 0 -1.1174 TD .0116 Tc [(ob)4.7(served.)-533.2(Two-)4.8(dimen)4.7(s)-.8(i)4.6(onal)-536.8(g)]TJ 12.7635 0 TD .0131 Tc [(el)-535.3(e)5.1(l).4(e)5.1(c)-.7(tr)6.3(op)6.2(hor)6.3(es)6.4(is)-535(r)6.3(e)-.7(ve)5.1(al)6.1(ed)]TJ -12.7635 -1.1116 TD .0122 Tc [(band)5.3(ing)-213.5(d)5.3(iff)5.4(e)-1.6(r)5.4(e)-1.6(nces)-213.3(wi)5.2(th)-213.5(di)5.2(fferi)5.2(ng)-213.5(pr)5.4(otein)-213.5(e)-1.6(x)5.3(p)-.4(r)5.4(e)-1.6(ss)5.5(ion)-213.5(l)5.2(evels)]TJ T* [(related)-277(t)5.1(o)-277(A)-1.4(2M)-277.9(i)5.1(s)-.3(of)5.3(or)5.3(ms.)]TJ 1.0137 -1.1174 TD 0 Tc [(Our)-436.1(investigations)-444.2(depict)-435.4(A2M)-442.8(as)-435.1(an)-441.1(important)-438.9(plasma)]TJ -1.0137 -1.1116 TD [(protein)-308.6(involved)-309.7(in)-307.6(ASO)-310.1(transport,)-308.3(wh)20(ic)19.6(h)-294.8(i)0(n)15()0(u)21(e)0(n)19.7(c)0(e)18.5(s)-294.6(su)21(bc)13.9(el)19.5(-)]TJ T* [(lu)20.7(la)19.6(r)-421.5(u)0(p)20.8(t)0(a)13.8(k)0(e)-412.3(a)0(n)19.7(d)-421.6(di)20.7(st)20.9(ri)20.7(bu)20.8(ti)14.8(on)-411.1(of)-411.1(AS)20.1(Os)20.2(.)-423.9(T)0(a)18.5(k)0(e)19.7(n)-421.6(to)20.7(ge)19.7(th)20.7(er)19.7(,)-423.9(t)0(h)20.7(e)]TJ T* [(re)19.7(su)21(lt)14.8(s)-381(o)0(f)-370.8(t)0(h)20.7(i)0(s)-370.8(w)0(o)20(r)0(k)-370.8(p)0(r)20.9(o)0(v)20.8(i)0(d)20.7(e)-382.4(va)19.7(lu)20.7(ab)19.7(le)-372.1(in)20.7(si)15.1(gh)20.8(t)-381.4(a)0(n)19.7(d)-381.2(re)19.7(ve)19.7(al)-372.1(th)20.7(e)]TJ 0 -1.1174 TD [(ap)19.7(pl)20.7(ic)19.5(ab)13.9(il)20.6(it)20.6(y)-208.4(o)0(f)-198(t)0(h)20.7(i)0(s)-203.7(m)15(od)15.1(el)-199.3(to)-198.2(sc)19.9(re)19.7(en)-199.2(ot)20.7(he)13.9(r)-208.4(A)0(S)20.1(O)0(s)-198.7(w)0(i)19.8(t)0(h)-198.2(a)0(l)19.5(t)0(e)13.8(r)0(n)20.9(a)0(t)19.5(e)]TJ 0 -1.1116 TD [(ch)19.7(em)18.5(is)20.9(tr)15(ie)19.5(s)-311.9(f)0(o)20.9(r)-312.1(ev)19.7(al)13.8(ua)19.7(ti)20.6(ng)-301.7(me)18.4(ch)19.7(an)19.7(is)20.9(ti)14.8(c)-313.3(d)0(i)20.7(f)0(f)20.9(e)0(r)19.7(e)0(n)19.7(c)0(e)18.5(s)-317.7(in)-301.8(up)20.8(ta)19.6(ke)19.7(,)]TJ T* [(an)19.7(d)-271.8(f)0(o)20.9(r)-271.8(de)19.7(si)20.9(gn)-261.4(of)-261.4(AS)20.1(Os)-262.1(wi)19.8(th)-261.5(re)19.7(du)20.8(ce)18.5(d)-271.8(b)0(i)20.7(n)0(d)20.8(i)0(n)20.7(g)-271.8(to)-261.5(A2)20(M.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 514.9416 Tm (Acknowledgments)Tj /F3 1 Tf 9.843 0 0 9.843 72 498.5006 Tm [(The)-230.3(authors)-227.6(kindly)-231.5(thank)-231.4(Ethan)-232.6(Weiss)-227.5(of)-232.6(the)-229.2(University)-232.1(of)]TJ -1.0137 -1.1116 TD [(California)-296.9(San)-286.5(Francisco)-295.4(for)-291.2(providing)-292.4(the)-286.8(double-knockout)]TJ 0 -1.1174 TD [(mice)-255.8(and)-257.9(for)-256.7(project)-257.9(support;)-256.5(Ezio)-254.6(Petrella,)-263.6(Alex)-254.2(Perieteanu,)]TJ 0 -1.1116 TD [(and)-257.9(Colin)-260.2(Barry)-261.1(of)-261.4(SGS)-263(Pharmaceuticals)-266.6(for)-256.7(their)-260.3(assistance)]TJ T* [(with)-454.8(immunoassa)-9.8(ys)-451.3(and)-459.5(protein)-458.4(characterizations;)-466.1(Andrea)]TJ 0 -1.1174 TD [(Benoit)-210.7(and)-211.8(Rajeev)-212.9(Dhawan)-212.3(of)-209.5(Charles)-212.6(River)-215.2(Laboratories)-213.7(for)]TJ 0 -1.1116 TD [(breeding)-270.4(and)-263.7(colony)-267.1(conrmations;)-265.6(Xiaokun)-269.1(Xiao)-265.8(and)-263.7(Gene)]TJ T* [(Hung)-287.5(of)-290.2(Ionis)-287.6(Pharmaceuticals)-295.4(for)-291.2(their)-289.1(support)-284.1(with)-293.5(histol-)]TJ 0 -1.1174 TD [(ogy)-308.6(assessments;)-316.7(Robert)-314.2(Saunders)-316(of)-307.4(Ionis)-310.7(Pharmaceuticals)]TJ 0 -1.1116 TD [(for)-481.3(his)-487.1(administrative)-487.1(assistance.)-491.1(They)-484.8(would)-484.6(like)-483.9(to)-480.4(ac-)]TJ T* [(knowledge)-284(and)-280.9(thank)-283.3(Donna)-278.2(Sipe)-282(and)-280.9(the)-281.1(vivarium)-282.1(staff)-283(for)]TJ T* [(animal)-517.3(husbandry.)-509.6(They)-513.6(would)-513.4(also)-512.4(like)-512.7(to)-514.9(thank)-513.7(Tracy)]TJ 0 -1.1174 TD [(Reigle)-206.1(of)-209.5(Ionis)-201.2(Pharmaceuticals)-214.8(for)-204.8(her)-206(kind)-206.1(support)-203.4(and)-206.1(help)]TJ 0 -1.1116 TD [(with)-282(graphics)-281.7(and)-280.9(formatting.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 332.107 Tm [(Author)-338.7(Disclosure)-330.4(Statement)]TJ /F3 1 Tf 9.843 0 0 9.843 72 315.666 Tm [(All)-643.8(authors)-648.1(are)-644.9(employees)-648.1(of)-641.5(Ionis)-644.7(Pharmaceuticals,)]TJ -1.0137 -1.1116 TD [(Carlsbad,)-286.2(California.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 280.8 Tm (References)Tj /F3 1 Tf 9.2951 0 0 9.2951 66.6708 264.7558 Tm [(1.)-500.4(Chaudhuri)-317(L.)-313.2(\(1993\).)-310.6(Human)-317.1(alpha)]TJ 6.9712 0 0 6.196 212.0314 263.1685 Tm (2)Tj 9.2951 0 0 9.2951 215.5464 264.7558 Tm [(-macroglobulin)-311.8(and)-315.7(its)]TJ -14.7662 -1.1284 TD [(biological)-336.9(signicance.)-336.5(Indian)-336.2(J)-334.7(Exp)-331.7(Biol)-333.6(9:723727.)]TJ -1.2503 -1.1223 TD .0171 Tc [(2)17.1(.)-483.3(Abe)-420.3(K)-2.9(,)-422.1(K)-417.7(Yamam)5.2(o)-1.3(to)-422.2(an)4.8(d)-422.2(H)-423.8(Sin)4.8(ohara.)-422.1(\()2.4(19)4.8(89\).)-422.1(P)1.9(rot)5.3(e)-5.5(i)5.3(n)-1.3(-)]TJ 1.2503 -1.1284 TD .0182 Tc [(ase)-535.1(i).3(n)5.9(h)-.2(ib)5.9(ito)5.9(ry)-530.9(sp)5.9(ect)6.4(r)-2.6(u)5.9(m)-536.5(o)5.9(f)-539.3(m)6.3(o)-.2(u)5.9(s).7(e)-535.1(m).2(urin)5.9(og)5.9(lob)5.9(u)-.2(li)6.4(n)-537(a)1.7(nd)]TJ /F9 1 Tf 0 -1.1223 TD 0 Tc (a)Tj /F3 1 Tf .5672 0 TD .0143 Tc [(-m)-3.7(acr)-6.5(og)-4.1(l)-3.6(o)2(b)-4.1(u)2(l)-3.6(i)-3.6(n)2(.)-339.5(J)-332.6(Bi)-3.6(oc)-8.3(hem)-339.2(4)2(:)-3.6(5)-4.1(64)-4.1(5)-4.1(6)-4.1(8)2(.)]TJ -1.8176 -1.1284 TD 0 Tc [(3.)-500.4(Rehman)-501.6(AA,)-503.7(H)-501.8(Ahsan)-499.7(and)-504.8(FH)-498.8(Khan.)-506.6(\(2013\).)-499.6(Alpha-2-)]TJ 1.2503 -1.1223 TD [(macroglobulin:)-528.5(a)-528.9(physiological)-531.7(guardian.)-529.8(J)-523.8(Cell)-533(Physiol)]TJ 0 -1.1284 TD (8:16651675.)Tj -1.2503 -1.1223 TD .0217 Tc [(4)21.7(.)-478.7(Overbergh)-344.4(L)1.4(,)-344.3(C)-343.1(Hilliker,)-344.3(K)-339.9(L)-4.7(orent,)-344.3(FV)-346(Leuven)-344.4(and)-338.3(V)-4.4(D)]TJ 1.2503 -1.1284 TD .0226 Tc [(Berg)4.2(he.)-410.5(\()1.8(19)4.2(94)4.2(\).)-416.6(Id)4.2(ent)4.7(i)-1.4(cat)]TJ 11.4788 0 TD .0217 Tc [(ion)-411.5(o)-2.8(f)-407.7(f)-5.2(our)-413.8(g)3.3(ene)5.2(s)-416.7(coding)-411.5(for)]TJ -11.4788 -1.1223 TD .0238 Tc [(is)6.2(ofo)5.4(r)-3.1(m)5.8(s)-402.4(o)5.4(f)-399.5(mu)5.4(rin)5.4(o)-.7(g)5.4(l)-.2(ob)5.4(ul)5.9(in)5.4(,)-403.2(t)5.9(he)-395.3(mo)5.4(no)5.4(meric)-395.3(m)-.3(ou)5.4(se)]TJ /F9 1 Tf 22.5428 0 TD 0 Tc (a)Tj /F3 1 Tf .5733 0 TD .0245 Tc (2-)Tj -23.1161 -1.1284 TD .0216 Tc [(mac)5.1(r)-5.3(oglobulin:)-350(characteri)]TJ 10.9664 0 TD .0197 Tc [(zat)-4.3(io)-4.8(n)-346.4(o)-4.8(f)-348.7(t)-4.3(he)-350.6(ex)-4.8(on)-4.8(s)-351.6(c)-2.9(od)-4.8(in)-4.8(g)-346.4(f)-1.1(o)-4.8(r)]TJ -10.9664 -1.1223 TD .024 Tc [(th)5.6(e)-334.1(b)5.6(ait)-329.3(r)3.2(egi)6.1(o)-.5(n)5.6(.)-329.8(Gen)5.6(o)-.5(m)6(i)0(cs)-329(3:)6.1(53)5.6(0)5.6(53)5.6(9.)]TJ -1.2503 -1.1284 TD 0 Tc [(5.)-500.4(Leu)11.8(ven)-559.7(FV,)-559.9(S)-570.3(Tor)13.7(re)11.5(ken)13.7(s,)-566.6(L)-569.3(Ove)12.1(rbe)11.3(rgh)15.5(,)-573.4(K)-568.9(Lor)13.7(ent)14.2(,)-567.3(B)0(D)]TJ 1.2503 -1.1223 TD [(Str)13.2(oop)17.9(er)-147.1(and)-138.8(HVD)-145.4(Ber)12.7(ghe)13.7(.)-146.5(\(19)15.5(92\))15.5(.)-152.5(The)-140.7(pri)16.1(mar)11.8(y)-146.5(seq)14.6(uen)13.7(ce)-149(and)]TJ 0 -1.1284 TD [(th)12.5(e)-321.5(s)0(u)12.8(buni)18.3(t)-316.7(s)0(t)13.4(ruc)11.3(tu)12.5(re)-311.8(of)-313.7(mo)12.3(use)]TJ /F9 1 Tf 12.6071 0 TD (a)Tj /F3 1 Tf .5489 0 TD [(-2-)19.3(macr)13.5(ogl)18.4(obul)18.3(in,)-304.7(ded)13.7(uced)]TJ -13.156 -1.1223 TD [(fro)13.2(m)-365.7(prot)16(ein)-357.8(sequ)14.4(en)13.8(cing)-358(of)-362.5(the)-363.9(iso)13.2(lat)14.8(ed)-364.3(sub)12.7(uni)18.4(ts)-364.8(and)-364.5(fr)13.4(om)]TJ 0 -1.1284 TD [(mo)12.3(lecu)16(lar)-238.2(clo)14.2(ni)12.5(ng)-244.3(of)-240.5(th)12.5(e)-248.3(c)0(D)12.2(NA.)-241.4(Eur)-230.3(J)-249.3(Bio)13.7(che)15.6(m)-243.7(1:3)12.3(193)17.7(27.)]TJ -1.2503 -1.1223 TD [(6.)-500.4(Hudson)-428.5(NW,)-433.2(JM)-425.6(Kehoe)-431.6(and)-431.6(PH)-431.7(Koo.)-429(\(1987\).)-426.4(Mouse)]TJ /F9 1 Tf 24.3359 0 TD (a)Tj /F3 1 Tf .555 0 TD (-)Tj -23.6406 -1.1284 TD [(macroglobulin.)-333.8(Biochem)-336.5(J)-334.7(3:837845.)]TJ 25.7571 70.9158 TD [(7.)-500.4(Armstrong)-359.4(PB)-355.6(and)-352.3(JP)-349.9(Quigley.)-359.5(\(1999\).)]TJ /F9 1 Tf 17.7061 0 TD (a)Tj /F3 1 Tf .5489 0 TD (2-macroglobulin:)Tj -17.0047 -1.1223 TD [(an)-565.6(evolutionarily)-571(conserved)-570.4(arm)-561.6(of)-569.8(the)-565.2(innate)-563.2(immune)]TJ 0 -1.1284 TD [(system.)-337.8(Dev)-335.6(Comp)-334.3(Immunol)-331.3(45:375390.)]TJ -1.2503 -1.1223 TD [(8.)-500.4(Wu)-291.3(SM,)-289.2(DD)-290.1(Patel)-285.3(and)-291.3(SV)-285.3(Pizzo.)-292.1(\(1998\).)-286.2(Oxidized)-290.6(alpha2-)]TJ 1.2503 -1.1283 TD [(macroglobulin)-437.4(\(alpha2M\))-433.9(differentially)-433.5(regulates)-435.1(receptor)]TJ 0 -1.1223 TD [(binding)-256(by)-256.5(cytokines/growth)-255.4(factors:)-262.2(implications)-256(for)-255.1(tissue)]TJ 0 -1.1284 TD [(injury)-343.6(and)-340.1(repair)-342.7(mechanisms)-346.3(in)-341.3(inammation.)-339.8(J)-340.8(Immunol)]TJ 0 -1.1223 TD (8:43564365.)Tj -1.2503 -1.1284 TD [(9.)-500.4(Petersen)-536(CM.)-522.8(\(1993\).)-530.1(Alpha)-530.5(2-macroglobulin)-531.5(and)-523.1(preg-)]TJ 1.2503 -1.1223 TD [(nancy)-509.3(zone)-503(protein.)-506.6(Serum)-503.7(levels,)-507.5(alpha2-macroglobulin)]TJ 0 -1.1284 TD [(receptors,)-377(cellular)-368.1(synthesis)-373.8(and)-364.5(aspects)-371.1(of)-368.6(function)-372.5(in)-365.7(re-)]TJ 0 -1.1223 TD [(lation)-338.8(to)-329.1(immunology.)-335(Dan)-335.6(Med)-333.3(Bull)-339.7(4:409446.)]TJ -1.7505 -1.1284 TD [(10.)-500.5(Hope)-616.3(C,)-621(J)-615.3(Mettenburg,)-614.2(SL)-621.1(Gonias,)-615.2(ST)-615(DeKosky,)-617.5(MI)]TJ 1.7505 -1.1284 TD [(Kamboh)-664.9(and)-657.3(CT)-659.6(Chu.)-657.9(\(2003\).)-658.2(Functional)-663.7(analysis)-659.3(of)]TJ 0 -1.1223 TD (plasma)Tj /F9 1 Tf 3.4095 0 TD (a)Tj /F3 1 Tf .5489 0 TD [(2-macroglobulin)-568.1(from)-559.8(Alzheimers)-566.9(disease)-566.3(pa-)]TJ -3.9584 -1.1284 TD [(tients)-252.5(with)-251.1(the)]TJ /F7 1 Tf 5.9407 0 TD (A2M)Tj /F3 1 Tf 2.1957 0 TD [(intronic)-249.9(deletion.)-251.9(Neurobiol)-252.2(Dis)-250.6(3:504)]TJ -8.1364 -1.1223 TD (512.)Tj -1.7505 -1.1284 TD [(11.)-500.5(Kovacs)-406.4(DM.)-397.7(\(2000\).)]TJ /F9 1 Tf 10.7164 0 TD (a)Tj /F3 1 Tf .555 0 TD [(2-Macroglobulin)-403.1(in)-396.2(late-onset)-404.1(Alz-)]TJ -9.5209 -1.1223 TD [(heimers)-341.7(disease.)-334.6(Exp)-331.7(Gerontol)-337.5(4:473479.)]TJ -1.7505 -1.1284 TD [(12.)-500.5(LaMarre)-458.6(J,)-450.7(GK)-448.7(Wollenberg,)-454.6(SL)-450.3(Gonias)-450.4(and)-449.9(MA)-452.5(Hayes.)]TJ 1.7505 -1.1223 TD [(\(1991\).)-707(Cytokine)-704.3(binding)-707.4(and)-706.1(clearance)-705.3(properties)-707.8(of)]TJ 0 -1.1284 TD (proteinase-activated)Tj /F9 1 Tf 8.3377 0 TD (a)Tj /F3 1 Tf .5489 0 TD [(2-macroglobulins.)-244.2(Lab)-244.4(Invest)-243.8(1:314.)]TJ -10.6371 -1.1223 TD [(13.)-500.5(Nezu)-413.1(T,)-416.8(N)-410.4(Hosomi,)-409.3(S)-411.7(Aoki,)-410.3(K)-416.5(Deguchi,)-413.1(H)-410.4(Masugata,)-414.2(N)]TJ 1.7505 -1.1284 TD [(Ichihara,)-371.7(H)-361.6(Ohyama,)-364.3(T)-361.9(Ohtsuki,)-366.6(M)-365.3(Kohno)-362.2(and)-364.5(M)-359.2(Matsu-)]TJ 0 -1.1223 TD [(moto.)-444.9(\(2013\).)-444.7(Alpha2-macroglobulin)-446(as)-442.8(a)-443.5(promising)-440.3(bio-)]TJ 0 -1.1284 TD [(marker)-342.8(for)-346.6(cerebral)-345.3(small)-337.9(vessel)-342.4(disease)-346.7(in)-341.3(acute)-342.1(ischemic)]TJ 0 -1.1223 TD [(stroke)-335.3(patients.)-336.4(J)-334.7(Neurol)-337.8(10:26422649.)]TJ -1.7505 -1.1284 TD [(14.)-500.5(Annapoorani)-385.4(P,)-375.2(PS)-384.2(Dhandapany,)-381.7(S)-375.1(Sadayappan,)-381.1(S)-381.2(Rama-)]TJ 1.7505 -1.1223 TD [(samy,)-381.7(A)-379.9(Rathinavel)-377(and)-376.7(GS)-382.9(Selvam.)-377.2(\(2006\).)-377.6(Cardiac)-380(iso-)]TJ 0 -1.1284 TD [(form)-657.4(of)-655.2(alpha-2)-651.6(macroglobulina)-661.6(new)-652.7(biomarker)-659.9(for)]TJ 0 -1.1223 TD [(myocardial)-466.2(infarcted)-468.8(diabetic)-463.4(patients.)-464.5(Atherosclerosis)-468(1:)]TJ 0 -1.1284 TD (173176.)Tj -1.7505 -1.1223 TD [(15.)-500.5(Ho)-349.5(AS,)-346.4(CC)-351.4(Cheng,)-345.3(SC)-349.5(Lee,)-352.4(ML)-349.1(Liu,)-343.4(JY)-348.6(Lee,)-352.4(WM)-345.5(Wang)]TJ 1.7505 -1.1284 TD [(and)-395(CC)-400.2(Wang.)-393.5(\(2010\).)-395.9(Novel)-396.3(biomarkers)-396.9(predict)-394.8(liver)-396.4(-)]TJ 0 -1.1223 TD [(brosis)-342.4(in)-335.2(hepatitis)-342(C)-340.4(patients:)-342(alpha)-337.9(2)-341.7(macroglobulin,)-339.9(vita-)]TJ 0 -1.1284 TD [(min)-261.7(D)-264(binding)-256(protein)-262.6(and)-260.8(apolipoprotein)-266.6(AI.)-260.4(J)-255.4(Biomed)-265(Sci)]TJ 0 -1.1223 TD (17:58.)Tj -1.7505 -1.1284 TD [(16.)-500.5(Yu)-276.3(RZ,)-275.4(TW)-274.9(Kim,)-275.5(A)-276.2(Hong,)-276.7(TA)-272.1(Watanabe,)-284.1(HJ)-269.3(Gaus)-279.9(and)-273(RS)]TJ 1.7505 -1.1223 TD [(Geary.)-379.1(\(2007\).)-371.5(Cross-species)-373.6(pharmacokinetic)-377.1(comparison)]TJ 0 -1.1284 TD [(from)-401.2(mouse)-400.1(to)-402.3(man)-400.7(of)-399.1(a)-400.8(second-generation)-404.3(antisense)-401.4(oli-)]TJ 0 -1.1223 TD [(gonucleotide,)-275(ISIS)-273.3(301012,)-275.4(targeting)-272.6(human)-272.9(apolipoprotein)]TJ 0 -1.1284 TD [(B-100.)-337.3(Drug)-333.8(Metab)-337.2(Dispos)-335.6(3:460468.)]TJ -1.7505 -1.1223 TD [(17.)-500.5(Geary)-354.6(RS,)-349.6(TA)-345.3(Watanabe,)-351.2(L)-349.7(Truong,)-352.8(S)-344.6(Freier,)-351.8(EA)-351.4(Lesnik,)]TJ 1.7505 -1.1284 TD [(NB)-244.5(Siou,)-237.8(H)-233.5(Sasmor,)-240.8(M)-237.3(Manoharan)-247.3(and)-236.4(AA)-241.3(Levin.)-238.1(\(2001\).)]TJ 0 -1.1223 TD -.0212 Tc [(Pharmacokinetic)-275.6(p)-3(roperties)-270.5(o)-3(f)-273.7(2)]TJ /F8 1 Tf 12.3144 0 TD 0 Tc ()Tj /F3 1 Tf .2318 0 TD -.0211 Tc (O-\(2-methoxyet)Tj 6.1541 0 TD (hyl\)-modied)Tj -18.7003 -1.1284 TD .0119 Tc [(oligo)5.7(nucleoti)11.9(d)-6.1(e)-340.1(a)1.5(nalog)5.7(s)-341.1(in)-335.9(rats)11.9(.)-347.3(J)-335(Ph)5.7(armacol)-335.3(E)-2.3(x)5.7(p)-342(Ther)-338.2(3:)]TJ T* .0123 Tc [(890)6.1(897.)]TJ -1.7505 -1.1223 TD 0 Tc [(18.)-500.5(Tse)-591.2(MT.)-593.1(\(2013\).)-591.1(Regulatory)-589.2(watch:)-595.2(antisense)-590.4(approval)]TJ 1.7505 -1.1284 TD [(provides)-335.6(boost)-334.7(to)-335.2(the)-333.4(eld.)-336.5(Nat)-335(Rev)-332.7(Drug)-333.8(Discov)-334.5(12:179.)]TJ -1.7505 -1.1223 TD [(19.)-500.5(Crooke)-500.1(ST.)-499.2(\(1999\).)-499.6(Molecular)-502.3(mechanisms)-498.8(of)-502.7(action)-496.1(of)]TJ 1.7505 -1.1284 TD [(antisense)-340.4(drugs.)-331.6(Biochem)-336.5(Biophys)-333.7(Acta)-339.4(1:3144.)]TJ -1.7505 -1.1223 TD [(20.)-500.5(Bennett)-391.2(CF)-392.2(and)-382.8(EE)-394.4(Swayze.)-390.1(\(2010\).)-383.7(RNA)-392.6(targeting)-388.5(ther-)]TJ 1.7505 -1.1284 TD [(apeutics:)-371.2(molecular)-374.5(mechanisms)-370.7(of)-368.6(antisense)-370.9(oligonucleo-)]TJ 0 -1.1223 TD [(tides)-643.3(as)-644(a)-644.8(therapeutic)-647.2(platform.)-642.8(Annu)-642.6(Rev)-643.7(Pharmacol)]TJ 0 -1.1284 TD [(Toxicol)-335.3(50:259293.)]TJ -1.7505 -1.1223 TD [(21.)-500.5(Chan)-375.5(JH,)-379.2(S)-375.1(Lim)-373.4(and)-376.7(WS)-373.5(Wong.)-377.1(\(2006\).)-377.6(Antisense)-374.3(oligo-)]TJ 1.7505 -1.1284 TD [(nucleotides:)-480.8(from)-480.5(design)-479.4(to)-475.4(therapeutic)-482.6(application.)-475.5(Clin)]TJ 0 -1.1223 TD [(Exp)-337.8(Pharmacol)-335.3(Physiol)-331.2(33:533540.)]TJ -1.7505 -1.1284 TD [(22.)-500.5(Geary)-360.7(RS,)-349.6(D)-355.5(Norris,)-353.4(R)-352.6(Y)0(u)-355.6(and)-352.3(CF)-355.6(Bennett.)-354.7(\(2015\).)-353.2(Phar-)]TJ 1.7505 -1.1223 TD [(macokinetics,)-412.1(biodistribution)-402.7(and)-407.2(cell)-404.3(uptake)-405.2(of)-405.2(antisense)]TJ 9.2951 0 0 9.2951 329.329 97.5118 Tm [(oligonucleotides.)-340.6(Adv)-331.4(Drug)-333.8(Deliv)-340.8(Rev)-332.7(87:4651.)]TJ -1.7505 -1.1223 TD [(23.)-500.5(Campbell)-610.5(ZT)-601.8(and)-608.5(M)-603.2(Wickens.)-604(\(2015\).)-603.3(Probing)-603.4(RNA-)]TJ 1.7505 -1.1284 TD [(protein)-549.2(networks:)-550.2(biochemistry)-546.2(meets)-550.1(genomics.)-544.5(Trends)]TJ 0 -1.1223 TD [(Biochem)-336.5(Sci)-336.3(3:157164.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (234)Tj 46.1699 0 TD [(SHEMESH)-334(ET)-338.7(AL.)]TJ ET endstream endobj 142 0 obj <>stream /GS1 gs BT /F3 1 Tf 9.2951 0 0 9.2951 59.7543 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(24.)-500.5(Valacchi)-445.4(G,)-447(C)-438(Sticozzi,)-448.1(Y)-440.9(Lim)-440.5(and)-443.8(A)-447(Pecorelli.)-444.4(\(2011\).)]TJ 1.7505 -1.1223 TD [(Scavenger)-480.8(receptor)-475.3(class)-476.4(B)-474.6(type)-473.9(I:)-471.7(a)-474(multifunctional)-478.7(re-)]TJ 0 -1.1284 TD [(ceptor.)-340.5(Ann)-331.4(NY)-332.8(Acad)-339.9(Sci)-330.2(1229:E1E7.)]TJ -1.7505 -1.1223 TD [(25.)-500.5(Umans)-267.5(L,)-258.3(L)-264.3(Serneels,)-261.6(L)-264.3(Overbergh,)-260(L)-264.3(Stas)-262.4(and)-260.8(FV)-260.9(Leuven.)]TJ 1.7505 -1.1283 TD (\(1999\).)Tj /F9 1 Tf 3.2753 0 TD (a)Tj /F3 1 Tf .5489 0 TD [(2-Macroglobulin-)-362.9(and)-358.4(murinoglobulin-1-decient)]TJ -3.8242 -1.1223 TD [(mice.)-367.9(A)-367.7(mouse)-369.6(model)-369.9(for)-364.9(acute)-366.5(pancreatitis.)-377.6(Am)-361.3(J)-371.3(Pathol)]TJ 0 -1.1284 TD (3:983993.)Tj -1.7505 -1.1223 TD [(26.)-500.5(Umans)-328.5(L,)-331.5(L)-325.3(Serneels,)-334.8(L)-325.3(Overbergh,)-327.1(K)-331.1(Lorent,)-325.9(FV)-328(Leuven)]TJ 1.7505 -1.1284 TD [(and)-254.7(VD)-253.5(Berghe.)-260.4(\(1995\).)-249.6(Targeted)-261.4(inactivation)-255.5(of)-252.7(the)-254.1(mouse)]TJ /F9 1 Tf 0 -1.1223 TD (a)Tj /F3 1 Tf .555 0 TD [(2-macroglobulin)-336.3(gene.)-332.3(J)-334.7(Biol)-333.6(Chem)-338.5(34:1977819785.)]TJ -2.3055 -1.1284 TD [(27.)-500.5(Sharma)-331.2(VK,)-326.8(RK)-329.9(Sharma)-325.1(and)-327.9(SK)-328(Singh.)-326.4(\(2014\).)-328.9(Antisense)]TJ 1.7505 -1.1223 TD [(oligonucleotides:)-626.8(modications)-619.9(and)-614.6(clinical)-621.4(trials.)-620.9(Med)]TJ 0 -1.1284 TD [(Chem)-338.5(Commun)-334.2(10:14541471.)]TJ -1.7505 -1.1284 TD [(28.)-500.5(Beltinger)-527.4(C,)-517.3(HU)-521.9(Saragovi,)-526.6(RM)-516.7(Smith,)-520.6(L)-520.5(LeSauteur,)-526.8(N)]TJ 1.7505 -1.1223 TD [(Shah,)-465.2(L)-465.6(DeDionisio,)]TJ /F7 1 Tf 9.1245 0 TD [(et)-461.4(al.)]TJ /F3 1 Tf 2.6898 0 TD [(\(1995\).)-463(Binding,)-468.3(uptake,)-466.2(and)]TJ -11.8142 -1.1284 TD [(intracellular)-471.8(trafcking)-461.5(of)-466.2(phosphorothioate-modied)-465.3(oli-)]TJ 0 -1.1223 TD [(godeoxynucleotides.)-340.2(J)-334.7(Clin)-333.6(Invest)-335.3(4:18141823.)]TJ -1.7505 -1.1284 TD [(29.)-500.5(Crooke)-573.3(RM,)-565.5(MJ)-572(Graham,)-574(ME)-568.7(Cooke)-570.8(and)-565.8(ST)-572.3(Crooke.)]TJ 1.7505 -1.1223 TD [(\(1995\).)-365.4(In)-362.5(vitro)-361.7(pharmacokinetics)-370.3(of)-362.5(phosphorothioate)-364.2(an-)]TJ 0 -1.1284 TD [(tisense)-281(oligonucleotides.)-273.5(J)-273.7(Pharmacol)-280.4(Exp)-270.7(Ther)-277.4(1:462473.)]TJ -1.7505 -1.1223 TD [(30.)-500.5(Bijsterbosch)-623.7(MK,)-617.2(M)-615.4(Manoharan,)-619.4(ET)-620.1(Rump,)-621(RLA)-618.6(De)]TJ 1.7505 -1.1284 TD [(Vreueh,)-275.5(R)-273.3(van)-279.1(Veghel,)-272.6(KL)-278.2(Tival,)]TJ /F7 1 Tf 13.8087 0 TD [(et)-272.3(al)]TJ /F3 1 Tf 1.781 0 TD [(.)-274.5(\(1997\).)-274(In)-271(vivo)-274.5(fate)]TJ -15.5896 -1.1223 TD [(of)-380.8(phosphorothioate)-388.6(antisense)-383.1(oligodeoxynucleotides:)-387.8(pre-)]TJ 0 -1.1284 TD [(dominant)-558.8(uptake)-563.7(by)-555.3(scavenger)-562.4(receptors)-566(on)-555.3(endothelial)]TJ 0 -1.1223 TD [(cells.)-336.5(Nucleic)-337.3(Acids)-334.4(Res)-337.9(16:32903296.)]TJ -1.7505 -1.1284 TD [(31.)-500.5(Butler)-480.7(M,)-475.2(RM)-474(Crooke,)-475.8(MJ)-474.4(Graham,)-476.4(KM)-476.9(Lemonidis,)-480.8(M)]TJ 1.7505 -1.1223 TD [(Lougheed,)-328.7(SF)-323.2(Murray,)]TJ /F7 1 Tf 9.5941 0 TD [(et)-321.1(al)]TJ /F3 1 Tf 1.8359 0 TD [(.)-323.3(\(2000\).)-322.7(Phosphorothioate)-330.5(oli-)]TJ -11.43 -1.1284 TD [(godeoxynucleotides)-193.7(distribute)-193.9(similarly)-187.2(in)-188.8(class)-195.9(A)-184.7(scavenger)]TJ 0 -1.1223 TD [(receptor)-457(knockout)-450(and)-456(wild-type)-452.9(mice.)-453.3(J)-456.7(Pharmacol)-451.2(Exp)]TJ 0 -1.1284 TD [(Ther)-271.3(2:489496.)]TJ -1.7505 -1.1223 TD [(32.)-500.5(Koller)-404.3(E,)-404.7(TM)-397.9(Vincent,)-406.4(A)-404.3(Chappell,)-403.6(S)-399.5(De,)-402.6(M)-401.9(Manoharan)]TJ 1.7505 -1.1284 TD [(and)-504.8(CF)-495.9(Bennett.)-501.1(\(2011\).)-499.6(Mechanisms)-504.6(of)-502.7(single-stranded)]TJ 0 -1.1223 TD [(phosphorothioate)-339.8(modied)-342.6(antisense)-340.4(oligonucleotide)-341.3(accu-)]TJ 0 -1.1284 TD [(mulation)-277.7(in)-274.2(hepatocytes.)-278.7(Nucleic)-276.3(Acids)-273.4(Res)-276.9(11:47954807.)]TJ 25.263 37.1382 TD [(33.)-500.5(Juliano)-363(RL,)-360.8(X)-361.6(Ming,)-359.2(K)-361.6(Carver)-366.4(and)-358.4(B)-364.8(Laing.)-360.1(\(2014\).)-365.4(Cel-)]TJ 1.7505 -1.1223 TD [(lular)-512.3(uptake)-508.8(and)-510.9(intracellular)-514.5(trafcking)-510.3(of)-514.9(oligonucleo-)]TJ 0 -1.1284 TD -.0177 Tc [(ti)-5.1(des:)-242.9(imp)-17.7(l)13.1(i)-5.1(c)-3.7(at)-5.1(io)-17.7(n)12.5(s)-236.5(fo)-17.7(r)-221.6(o)-17.7(l)13.1(i)-5.1(gon)-17.7(u)12.5(c)-3.7(leot)-5.1(id)-17.7(e)-223.5(p)-17.7(h)12.5(a)-3.7(rmacol)-5.1(ogy)-17.7(.)-225.3(N)-1.1(ucl)-5.1(e)2.4(i)-5.1(c)]TJ 0 -1.1223 TD -.0175 Tc [(Acid)-334.8(Th)-17.5(e)14.6(r)-337.1(2:)-4.9(10)-17.5(1)12.7().7(1)-17.5(1)12.7(3.)]TJ -1.7505 -1.1283 TD 0 Tc [(34.)-500.5(Geary)-183.8(RS,)-184.9(E)-185(Wancewicz,)-186.4(J)-188.3(Matson,)-185.9(M)-182.4(Pearce,)-187.7(A)-184.7(Siwkowski,)]TJ 1.7505 -1.1223 TD [(E)-252.1(Swayze)-255.8(and)-254.7(F)-253.1(Bennett.)-257.1(\(2009\).)-255.7(Effect)-259.2(of)-252.7(dose)-254(and)-254.7(plasma)]TJ 0 -1.1284 TD [(concentration)-245(on)-250.4(liver)-244(uptake)-246.6(and)-248.6(pharmacologic)-245.1(activity)-251.2(of)]TJ 0 -1.1223 TD .3154 Tc (a2)Tj /F8 1 Tf 1.2625 0 TD 0 Tc ()Tj /F3 1 Tf .2501 0 TD [(-methoxyethyl)-321.5(modied)-318.2(chimeric)-325.6(antisense)-322.1(oligonucle-)]TJ -1.5126 -1.1284 TD [(otide)-272.2(targeting)-272.6(PTEN.)-271.2(Biochem)-269.4(Pharmacol)-274.3(3:284291.)]TJ -1.7505 -1.1223 TD [(35.)-500.5(Geary)-372.9(RS.)-374(\(2009\).)-377.6(Antisense)-380.4(oligonucleotide)-377.9(pharmacoki-)]TJ 1.7505 -1.1284 TD [(netics)-403.7(and)-407.2(metabolism.)-409(Expert)-405.2(Opin)-404.1(Drug)-407(Metab)-404.3(Toxicol)]TJ 0 -1.1223 TD (4:381391.)Tj -1.7505 -1.1284 TD [(36.)-500.5(P)15.3(r)0(a)17.6(k)0(a)19.9(s)12.9(h)-238(T)0(P)19.3(,)-237.9(M)12.8(J)-237.1(Gr)20.2(ah)19.9(a)14(m)0(,)-225.5(J)-237.1(Yu)16.4(,)-231.8(R)-236.7(Ca)15.1(rt)22.4(y,)-225.9(A)-233.5(L)0(o)16.1(w)0(,)-221.4(A)-239.6(Ch)19.3(a)13.9(p)0(p)18(e)0(l)20.5(l)12.6(,)]TJ 1.7505 -1.1284 TD [(K)-471.4(S)0(c)17(h)0(m)24.5(i)0(d)18.6(t)12.6(,)-475.8(C)-474.6(Zh)22.2(ao)19.9(,)-475.8(M)-475.1(Ag)22.5(ha)19.9(j)12.6(a)0(n)19.9(,)]TJ /F7 1 Tf 14.4735 0 TD -.014 Tc [(et)-489.3(a)-14(l)]TJ /F3 1 Tf 1.9518 0 TD 0 Tc [(.)-469.7(\()0(2)15.7(0)0(1)24.1(4)0(\))21.8(.)-475.8(Ta)24.1(rg)15.7(e)14(t)0(e)20.5(d)]TJ -16.4252 -1.1223 TD .012 Tc [(d)5.8(e)-4.5(l)12(i)-5.4(very)-372.4(of)-374.7(antisense)-376.6(o)5.8(ligon)5.8(ucleotid)5.8(es)-371.5(to)-378.5(hep)5.8(a)-4.5(t)12(o)-6(cytes)-377.6(u)-.3(s-)]TJ 0 -1.1284 TD .0108 Tc [(ing)-239.4(t)-1(riantennary)-239.4(N-acetyl)-238.8(galactosamine)-237.5(i)-1(mproves)-238.5(p)-1.5(otency)]TJ 0 -1.1223 TD .0117 Tc [(1)5.5(0)-.6(-fold)-330(i)-.1(n)-330(m)-.2(ice.)-336(Nucleic)-334.2(A)3.9(cid)5.5(s)-335.2(Res)-335.2(1)5.5(3:87)5.5(968)5.5(807.)]TJ -1.7505 -1.1284 TD 0 Tc [(37.)-500.5(Juliano)-363(RL)-360.7(and)-364.5(K)-361.6(Carver.)-366.4(\(2015\).)-359.3(Cellular)-368.7(uptake)-362.5(and)-364.5(in-)]TJ 1.7505 -1.1223 TD [(tracellular)-337.9(trafcking)-333.4(of)-332(oligonucleotides.)-340.6(Adv)-331.4(Drug)-333.8(Deliv)]TJ 0 -1.1284 TD [(Rev)-332.7(87:3545.)]TJ 9.843 0 0 9.843 438.803 494.1353 Tm [(Address)-331.9(correspondence)-343.5(to:)]TJ /F7 1 Tf 1.5609 -1.1116 TD [(Colby)-336.1(S.)-332.8(Shemesh,)-336.7(PhD)]TJ -3.738 -1.1116 TD [(Department)-337.7(of)-330.6(Pharmacokinetics)]TJ 2.1656 -1.1116 TD [(and)-331.6(Clinical)-334.1(Pharmacolog)-9.5(y)]TJ 2.1772 -1.1174 TD [(Ionis)-333.7(Pharmaceuticals)]TJ 1.0598 -1.1116 TD [(2855)-332.7(Gazelle)-339.3(Court)]TJ -.3513 -1.1116 TD [(Carlsbad,)-335.6(CA)-332.7(92010)]TJ -4.723 -1.8719 TD (E-mail:)Tj /F3 1 Tf 3.3982 0 TD (cshemesh@ionisph.com)Tj -14.549 -1.8777 TD [(Received)-412(for)-406.4(publication)-412.4(February)-408.3(2,)-407.7(2016;)-408.8(accepted)-412.2(after)]TJ 0 -1.1116 TD [(revision)-332.6(March)-337(3,)-332.8(2016.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(PK/PD)-340.1(OF)-331.2(ION-353382,)-332.4(A)-337.9(MODEL)-333.5(ASO:)-334.7(IN)-335.1(WT)-335.9(AND)-330.9(DKO)-337.5(MICE)-23255.2(235)]TJ ET endstream endobj 146 0 obj <>stream 8;X]O>EqN@%''O_@%e@?J;%+8(9e>X=MR6S?i^YgA3=].HDXF.R$lIL@"pJ+EP(%0 b]6ajmNZn*!='OQZeQ^Y*,=]?C.B+\Ulg9dhD*"iC[;*=3`oP1[!S^)?1)IZ4dup` E1r!/,*0[*9.aFIR2&b-C#soRZ7Dl%MLY\.?d>Mn 6%Q2oYfNRF$$+ON<+]RUJmC0InDZ4OTs0S!saG>GGKUlQ*Q?45:CI&4J'_2j$XKrcYp0n+Xl_nU*O( l[$6Nn+Z_Nq0]s7hs]`XX1nZ8&94a\~> endstream endobj 147 0 obj <>stream h,M%GEF" $" e07wowQ]_]L6 " DĕK{X?Ts~kխ[N{{w_K?>ӯpO0ׇg'[ Ӝh PUhjؐ6[Lezk36nr BB$QzX]=:o2Ek|N3v&ޔ?(mչ>7kq.ې8)a|fA;<YhJ^]+]M&RdҐt$3xs /pşo\sk_9glX:V.od"#âhI \ibdW`Ŷͣ6rPrvpF Yܳ'*鈻 8aкw`O}, endstream endobj 150 0 obj <>stream hޤV PTWGDA5FE  b$A d,Q6( ƕM@7d3QIpQHs̼FcJjjo۹UR 91$8Ⱥ6Ta*e1F'aYQgdSfF'Me'd]PbFAk2t  >ː8V JMi0#VgRs Y) z]Ie4q.#Ii=ӧ'zgu)B֔oJILS bT'PII$WI#UhKJ4$[ Iғx)DKҿTT3UbgSfilm{4vvN @C kwǪרR5CC~R(NIrAvxu]U{uyj,a`2eBe9[,(Q :c Q:?ܢRՙ PKxK?Ȼ7exΓ2z>4;0d. 0,S2|Lij߶wwvu;p Qꍥy@^Q &)Dc`8F0HY=.piϡsHo=8GD:h% (3UПZR]Ryphkz5IՃO4~|h=5xGat`xgE;WWfNgm|e|u۫ yڙ HϢ7 ]^g#q@nv?F#^q!{c<6rxCVxϝBs^;WmرzZڊ3Q[b`0a`#}@/c% 6d7dQ7j0xE`[S{qà႞S8z.jEpc0;D8".2r;j?k߫)h|/5dH-jӕm'y&/Y`P/as9t( F+ɉaQӠg ł#z^/kn߸K=5.^g?<_Ge\G`ydSlKڵ[xURZPPZ&N'2t\d?&6)zޢżSE[ G>ao^0=OïŲr+")hk 'Wfv@.0] e<@zb;H>4{Y?7n?s Pz]σ[^۞(OW0ډMfjaxjhuE;P)#K u v/W `2xBIЂ3絨!sDgwsMhX)H~[B8!wYM<׼ȴ_VdE f%B-~eL%tk K 66*/kI*]ShZUjP8&SqG[aVX \r#2ľ㼴d>e I`{Z(^T2Zkq'BM)FM ē6 n+Roa9JP8&CABa/c=[ Ӆ1$> ܄MB )o}J@m.ƀl 0S=j>+Oĕw+0,R endstream endobj 152 0 obj <>stream LDDJHL+AdvP4C4E59 l| C22AdvP4C4E59 Blt9m endstream endobj 154 0 obj <>stream 8;Z\7>7uQ2%*\Z'R-Si6:a+mG"rOK>@F=(th1UQ>+$'B)EEkH__C29`"A8U=J^a7n Q1)jp5eb%]8)['C"PP8&giOAYN!Tsb,n!:"pAb2S`n?ZF:(9Vqn+>!#;:tU4dLR>& Pc930R3OJ'b\**toI^iiq'c>i?0^OGb3%7'_Z7\0hl7M'UT57` f$5;V29V'8)Z.%WCQ=$_kuhoYDiLuVGos+bqJNtdQ`[M0XuTBC`\/nDj*^(?fR='n )YLgFZ&\QO+b.D:~> endstream endobj 71 0 obj <>stream 8;Z\7m;<"\#g<+[+KmRqe(->m*0ZFa;u+ht.:?t!dr8okW'kETP2A77kr"m=0b722"&3V4*BH%YC.>$RDP"hcP>IH 9@!)g?<`DhpdI*EKEY'5CqHXNbpHXp,DN4.>rd[h)M-@51,lZuC^fX%fDY,Z=BY5? Ia,5llkoDIKFoa#I8T%s*bs_F*#FH=+toC5Cu1G%OlRDr'FUhlmOIBG:fCc-BBiK`4\A>.R-/8>%#Iu^]5!;e.A>6~> endstream endobj 83 0 obj <>stream 8;Z\7=gGpf%"%``TWds9RKTiGDkucBif?b87[Ct*.e5tNra'UD:r1/cO(Th6BqBE: rrueM<#88]nOdN>:)#@!e[g5j0TF-e#Kt\X/'U]r&sD#Y:)W,U"719lc'IrOV8:g?hW?;P lHLQJB7?H;FX%fpM'ia<^YE);/h965rY^VfIoh8::J,Q><\RT?Ei&33Jjm.+21k:/ 9V]hROI*_;\eBd&R,MVhnZ5B,@kApL"4kceMI6thqGl/`al);nSEBG(?,/3t?a(l9 1M(qo*o`b)pq4pdA;Rn5>5A\Wg"[,^\F)LE]`%u9&CrF^)(,aRB;3@&hC";gRcMnM KYmA2(j`%Rr0l9;dCDEZYUC2:jF6Hp&`?aEYI/l4;W')o!!(3Z]Ib[SR#gs6mT8j` pl")JmZ+CSi%\^oQYY,BZ*s1cX(gc:;Wg=_V%jPWXKe#)>(aJ2qPD!-WY&>@l\Quq nNR"BRfgk~> endstream endobj 89 0 obj <>stream 8;Z\7>7SOn%-.='b]WWacC@p!n;k:$h_S7g,_NF.Eb?)oO7I?2Ab ejQ;0G\t>*Q^Z-V@GP:1WUaEk>)eK7D4DCXd9i:-)8$ZOQQrqRm>=JY<]D8;$A:9[ !>Xmto:]cS0\FcqniBOB09jMd>N>)i5/]KR!F@"'n@JR__m+X?fpXa(K.R'DFq67S W?[D`KE,MCAKsR(#`4LN#\+;!dBJj5b2e['CUreX=^c"R>ZJR7AGS(CJ7N$"&Q4pZAP/cX8V=@`&!M56'5fK[S7C#7mi8flH%FWm4*>6pa 7n3C+J$_b#-T]W8"jS7p%':TJh)-G][L(?!A!ILB2Rk?+pXT3G[#+to&+#GY`ZN-3 !9FXu1&~> endstream endobj 102 0 obj <>stream 8;Z\78J8op#j_LTaEMr%40]C7_BeLlS?`\L.:073'8:ZOn\&nX^:fTj:<\;:\PW,5 GW>s8*<]2="$?pIq)#>lFWo;VLhpLB#,RgN%StCAeXU*41j3P_/8nf10%?9Edj!9b GB[Di)Z7>q6j'e@2gf\OBNhjM:;j2AgR@/8o3C3s^S"%MYY/)LSW[@SH%9q];XF=S 3%!R[+*l=an0`\04-AI'l5*+&iCE8.-6%C:)V;EZ269=rB1@C#V&n,CY%*U]`_W_@ 2pQ[HTjR6$5MSepKoWf)\0"o=$qil\?ts.D`+eMf@RhDaTjDUV@i1+GI%mE2s->Kj [Y]"[`,m^e8Rm>un.p$VT5*1W%5C'VYpWRsXX`3**+S*L^tb/HM*^MaG$&MF!Pi@t @l^>jHSDYe]T^^6Z"P5P@'rU%$B#g6XD"p/g:ch,Y$Z!/O,qJ5TlVa$MY_%-^, endstream endobj 106 0 obj <>stream 8;Z\7dBUV4#c&R>Z(LYu5IC#7)82pL.\Q7TboAr&0eU'gC4c3i9)of`PW6JA0B*(Y -b'^TZ?+j$nV%]!;Aer8SlUfl$$s-r*=\'ZrE+#pD+B>ViUpBI:p8G^CtM`4J@RcV ]E%_4`3U=ER+njXRp1s8>qU8EYZefK1FH[D_p#8<=IXPXIJFe@.ADl)c)i]N.AuiD Xie9+8t&di)%iMUg(c*.E'K<#<0DE)UM!=][#dS+JGu.TbY+Z7=Sh*Xe^XP6Xfato loA!n#KQVXEi9qR^2*gECY*c:5lFh. jeh^IA^]F\cDWd_I^)9.l-o4W\PEC+*V4R5jT0.'?Z"U`03md]YG5B%qJjo2"-gEF DBe<^D,Kp/$;@)*O0=`cQ[%I$NU'^%7#4t]V;(s3kkR'D#di@'f<.sd_=N#'@a2-W X>fsT]H*E= <;'m3;"I=Nht88gM&:I&Elgn?_aDO=SQI^m9uLuKS6NWUi3>ZC`/JctI\U".YPoXh hhBn_ endstream endobj 112 0 obj <>stream 8;Z\7$aT(@#\?6eL]+G!p>^=&!<:HF]kurgR7jGp$jI20%iE0U]H@b3?ej`,g$dmI S$8,mBiS&dJm[VSf>).dk$)4;B_ (PQ:,>?_E#kl,9;n.>fQSCgF]ZM2eV]erCA)@pIMHLT)C*(=WPcmBtX5rEH<%@5) )i<[+OF(hJa/A/Y[K>V6L`*Xs6.lB%T_SYA)rD?p*0Snu*M(o18Mufh3-^BtrdaS$ 9GO4-jeWh38IAu^_ok[.5tp*(>K0krdQC[QXBPn'2q4F[P`k0%banL4XR/CDC,gI[ J3Em0>S`8^V&1YjA#(2C^(3kAnGt>H#@5h](T%QTS#m];Kl!f]9KDYW>h%c5D0[.b ;d;)t'l%!ZOY7dMpMPtb+B@u?XHHhHnpKNl9l0Q6LnUtX`Ik@&B(kf+`[&:"m_1"$ 4"VA//ba*rp*1*NX:TVFR"h&-.:!J3>\s`F^'m/J#DZrZ7oY7daDG59Jiee@qQRc, d@BAs4K571U2FO0.:VN(,td[:?#6%XG"[6YEP?t=l)'n ?>"'MAC5l_^)O3sY)+L:&5uZuhOJ^[3P`&RInEc;3l1K/>@DL4UMg'4o2QI^=C5+U O7F$S]0fdmHb7;rd endstream endobj 117 0 obj <>stream 8;Z\7Mm7mW&A3JULOSHBIV@nY,Rtgg759'D3@DfP/A'(GRSnSh'*&\5hQ_UW7jC`e akO'(Ce&aKN\MM*oda(m&>B>fN\JG2^&`8X1#N*dfT#,O-5/:i%I:eh:9O[\0E54Q 68)0^/:p(Z>L\a2ll&YN7Ur%+WoNd`/mUD:hJpsLAAKJLd$SlYKDQq2'%=LNS?!hm -WZDq).TKVlO_^-Xdl>q^f[ulift"tY(j5jZ[$b+mLNXg,o$F^3\"0dm/_2R8\QO[ SNOQ*1IC8GY)e,3AG?*CinRV)/QR]0nd>Hcb5tlJ-@u<:aK>=YE=O"QdT#Sk)10a)uNlQQnk!Z =U,TE5:5pS3_ENAise6<]N@X0$Z33?\rLo:k/JV%,mmh2k-]s0IMO%[1%mQ(aS[` endstream endobj 122 0 obj <>stream 8;Z\74dr-"%*a4QD0?FF*NnNKaVHC.\Hlm\9t6#8T^/[)S"DBkD4""SrC.G%-MGoP /3OiEDqe]UB[ap*9aZ[E,oF.fQ: f=!%-i'/9je8WjWKV0K#&q3^&K?(@91i"BgR)VC21H81SoAYRiQOT(0)?^%Z(h.C4 ]QcClKUH5SB#;i-?A&d`A),*)E#(.Li$"a>+JEM'"Z3g;@"Z*,r'Aru:@R)bBYieU 3R6)NV_us`O&QKO$'B-8b+dpWV(UYV&.5cS%%q#O1Y+eB=!&9uEQ4g0rH055S+hQ" &)\YfBY,^;3@sl!:[(,Zhodh6pAR37W*O;M+TY!Ke'k_:pZ[s_%X!A?*8 N%J1fOX2J9FLh\k[,42AD[-C6MLt[53c[7Up5Q6bVlId%_*Jj[0dd1bqMGdiOUdFa lqGYnf`4+B]#ZBBm3Fd05m\OYpioW+i*^]_"IMKH\EYpZ,<:m0iME2. Imd\DQL(.ZZ55]+'=o>/U_L[roL9II+U?^h-F!&IV:td8k'r4fK^Vo8<=NpR2+q(P bn']tW8e@\^T4ME?.88JKkkE#PeIqu,K?q]o)Dgp$>q5mVjChWq0I%FFQ]ZS=*j9m X=oM$,E!qh\8<=#hr0`9ASCVg//7]"0'F\ElV8!1@nb0B]D4Koca5jJ(+lsX?Wf73 AW1``;>593k0*X@ endstream endobj 128 0 obj <>stream 8;Z\7Mflo[%+IK-_`ldEqlih4@_8:o&R`5mCT^AR(2uHc&8=aDMu[6nbDmP649`*R?pW>_`4MCN+_g:IL$I]BrU-mZZcq"bQ] \ej&?ad(m9S&6FA9gVc^;%*7,oAt]`Ej%l.>hq=uH`_a\KZ7`k5T&ssj#[EXiX:IU KiB.TP:H]@GOOd<&(gXLNW47Q,".n`P:'Q5P`PRLGc<;3QWUX7'JbmB,N:$$4r*t5 #B(Wd`!m.t%F2HH'8iGH?&c7U>^!&M>S"crVp"'t[u#_;<@_.])X2A/H6ch:FCGXW *VqO8QH"rU%Q9;L%T@6$#.Fc:HN3tHcC>=3N>FMURpa-#\."_C"Tr"2i_!K#IT'Ko 3`tb1,!"RF3k2\i5Q#9EKUZfddodWqWQIkJd*!]e endstream endobj 133 0 obj <>stream 8;Z]"$b#@D#XpNkk2UiV&+a3j&,ZuK6qs,YGJ.#)gX!:\3cs@3"?30huk&Q\^/2+;Qf!$gCK:Sa4.o .u:L4aE/jS5Z%2`cGH;#$/jM]X)Xhd3(RJ\lVP8%<-/]T-#V=VJU0&TN(I_0[LhLo AEgD!f%WG+\%2\c^,JK;6aYrZGce-/70B9UJ/YtYj)n.oDAC*%]rJqO85/Vj_V4\@ aen45W*5TrjbZ[k/hC-15X+MnTe=NXU`3;:Kk!Ld%m6kGGj#R_6dc&:rJB3LiL/q= /GJV""0aEV5-V+7N3(MZ\D%$I>stMj6sW)>U$BIa[tWm%]n.eBBa:@ppD-WM m@WdRHR0K&d=l]`O#^Hs<<_=9*q?J:XMQB]AsdO'CDJ2W.k2NHm]3>1^3G:.'pAk# )W\*Aer+^hET4m9Wp@)[8!:lnD=WAeMqq1"O`0@I=rle-d9"'NZ+6&H+!"Auqf':# =`;Mc>;oVbDl9[l3[aW'met'`++nt>=)2K?osdN$B8q'*I?3d?rQ1gUhWTGAlg]A) H(=/GS98'1j(V]1nt^D5naK6?9-VF;%qM`U%Gg[/>s_n)6gh&i?W#0?gb[n3hNEpM cuGVJn5uqJ>j=.lI%=O.P3a,/I1qh'5&9r*aBNCdp?6[MpZ:]W^TdJl!"g0P1&~> endstream endobj 139 0 obj <>stream 8;Z\78JZq$%/'T9b]ULq!sq1:U"u)q^4Lid7O3;\;TDXZjJiZ8G19rd5Q3`M`-LGe qZ12h\;jZIiJ,#=`T=:%6`VotT2f"BS"lE!BTWW[S%R4.sb)2jM'4e&'i7mLY<%>;Mh*KJ8kVJKan3 flQ=NPR;Y7adj3]F^J endstream endobj 143 0 obj <>stream 8;Z]!>n-r[#__sO(Z[X%-N4AY'`68$pTeYS&I)O-#R#AZmDjr>pNLn36`j+^Of%(h k]1FM;TL1hnW5_YtH* >&0HUL9sY3_8'CE;eQKGCF-mM39Ol)>0@fh\b?mHZ)h="GgC)bgP9sSAD!GVZD1WN eY>QLS6[P,l:gYAm4/VVn]GqJFVp-R?$0dm4:ph($%0h8eqUQu;K;/D47:A:+N)-; G?SqQ8PU19h`UuN>bq'J;6)ZCMO(a$]?GIuYDl?OBS"ob2)Rfp>KFF@F(Sm endstream endobj 159 0 obj <> endobj 160 0 obj <>stream Hn8".i4-nTC G€M|~Ϯ$Yw$$Y>H5*s+2daB_f?|cڭ)پ*ӌ12nΙm!1E7jmq] KMYL`y ᛧQo)!Ff(mVޞ]]7mjeس \gWuXec2ݚmu8ԕ*OʽN.oӸlf_]S>7CwV۪aXK*!*(3+}l]܏D G-6vk4S|!.0/HĒC!PcD#".}N #}U^^(G߇ $ ^Q[HVZK@rtmn o}$ˡjLR*6Os*4fb0Hc6ApXBŸ/~iF]Nй?`ߢs~5_=LЅupν*x cOLdVޖaU mc=O~mMI `Xs8o쟭kL4UrcK.'Jb*FW adc;*`#/9GSw<ȔM~?Pq}X6UUϺ*P _Fmwt<Ϳv1 IeTx!eJee$xjZ?;vNP=ƅ!AM]eA7\{[F|z\*~x@狻]CNA|J}^ mPkK҇Q`Y Ѕ>Ʊ@7D ۹τ2p}T'7LR' endstream endobj 161 0 obj <>stream H\UKrF )lLgT9ǩfѢbG$!ќ2'Y4T.ywO߿Smvn8OMe;uPKg6:Й<6r-KW?pÑ^/;2QpBm[$9JUj]]P'̤XEB+/f">vʌ!Tff;:v́=/fz0\&_S-~"LK$T In+WKTo*bU.*4 L8H) uOmpnY7}ml"# UFP%nɘvߊqNϽn$fM'=ڪVO_ (;nVN JwņZ5z)դOgơ#؃Ӆ۫}tFhHv( .lgRC} nvvRQ/wgknCB3Xf4X P>>2_G7/_\̓]mof~ҳT&]|\}zak61A&y`=3 zII@%(98h>qۈj`EF _$FC\ҢZC(u7vRmVBZی!գ`4ShnD2/8TPNpTr (96B=[ghjD5+$guc˅% ^Դ1)Nt}*rAS( Z)"&3G3zӚk3t0qV&+C"Hbn{/mASw̚# \6j"\I 1lrW!Ӑ){ # xKSWN,(Czkc^U+~ endstream endobj 162 0 obj <>stream HUn0+tZX4Ez-AdG, ?ol\@Isf8ޛFG[LQSlĩKU~(\5ZuI Xjƨi=H$JbT~Ʃ{<0n9I)ik+dbBC+1fԯO6WAgƄ4!I7ؖj r@CV2zd"P^+7m@y 9j $ >S]pHïHlef.)"\&Yihwlmrx1:\YcG~J@[X(R I/Jf.܊_'!{/y=r' }"0D} Ve}cѳ./, w2PD~s7^cTjYsß6ʫ^GϙbLܴ<Hf%iʦ 6.QQډ/H`qu A/$-ÙfVf^ztL2$*;PpgOOPMT,ɵ)ZBaP ߌ2+, |!kF~}D-)wr<&.j32@W=!|ZUY8* k{<R",Š͇:9u-3K+cx}E64h8%e!,X Յ,Kp+П{ endstream endobj 163 0 obj <>stream H\Uˎ@W8Df)E{`1QCS2ޜ`fi鷫F:h44sF+$c//ptE^9^O✸|RE1=F>AR,~E>u?` IS`%n$gox%~$;rQOK)|츝P(e:I ] S WGՀ4dY03G+tN bI =)"UzAH:>TÐ5J˅MNpoJk>޽pZD&P|'}''5rY*qU~w2u#HAtEB` z((RKKG!tWسytTo4Ykhk5~/*,9UaҸ˦?Esm@2,rLÒNp*i3+֏l"cjB,=*.m+E{ jփDXjcy ^YVZҫ&ZV$>bqe~jFQǀaZ?(74"NAurOt endstream endobj 164 0 obj <>stream HtUM8 WkՒe>X^8Y2"(gv]|$#(ۡ1t,knJUɹPBÁ5snx:IRs!P^BDɭ敢t25WURU\.Y*R0/*p:y`@ .t-`9}l`j;otʴ/˳pȠ*6v!97FcAQ( )aś9H"Fprz4l;Ҽ`5>l?J”\ŷ'⧱#zGnVO@@GCdJXK̲4~wJ!$@y!O,_%׸z˴Ѷp;^dS4ӇMބWi##V=V| vKYu rI!!Va$T5O}L p#+(h'%*Y34.hFSn2&^5֖FkbhuX<ezIF x4n&&=ي~JXSGvXnMwl)LZ-݆oklj#j$_<%"WaqD.5ykHD9cFMm LFOأ%:tRlQCP+,xbwX/"KRsa<fߣ#^!mlD?n!.SJ}C 8i>!*X̘J{@J#c {0y< 9Ib9,n- 5GaSζ4\{OMz*vs}Uh.ZOHAg1LUEL;h'λCGeo^ǒ5(FK"4 endstream endobj 165 0 obj <>stream HlUMo8 W,&Fd)80[уbfe+oY>i2@o4I~txJJ]s'ϧy5" ԏ:jr{GZ4uJ,uQ:s,|v^rKoN%(QNr5{2tH(Sgb8\$ab)0lc,Iy&w7`GB endstream endobj 186 0 obj <>stream h t|T>stream hTMo ;@BM5)}hv'dH AGiЃ/msk&yA6<-N"t8h%^閣@Ce='kBCrnᾸ:m]ˏ,~CžY1"XwVHt 58ݞ?GsE/HV;*9!0+*`)~dEc8 iIu,qu%¤Mssѱ۞rq.XlMvqxȏ endstream endobj 166 0 obj <>stream HlUKo6WH`>$JYEzrYPɯ )PH/3?+V7w!\H!S>;+K/dJHN] n;wr]Ψy?;F#&GqU]t([>3:u#|U~Aw's>i~)l+abKQ8:npKȮAjaHdQ/NDAoo%JdJƇl>?Lϗ-$.cpH7hEAmM<4Z5Dlߏoy嚄~F"ԨU'>stream Hn@y 7/Ԗu F+NR +~yuR&1A\M~]^4B]v`;[ 0Bs~f6=IsȕOo"i+[fbu۵;GO4wYnCFEbc }HNNX ܗy[qCQ(jo-mTi^-!afz1Ԟ&V j.Xoht2ݬbl [,wf.,"Np+3&갻/۸:Ά !Ռ{b@\S=˺B.BI] PsaWcΟy7xT;zqo C+)|=jl`u P endstream endobj 173 0 obj <>stream htX TWV *¸]q_PQAQqQwٚnza_f_eQԸE[b&N?3N\r_?9uN>Uf0[[[u[o&X+"fGlGDH`Hm gky{\PP6Lf]޴fk[Ҹ.6N.uz/hӂK>m/~u_j/&860i"Q~0(6!.6!@)oƲ2Xvdh:e)ԹΚk;FC$Jp?f~o2k={Yy}e0ed/=>rힶXėkx獁 ٧<޽! |XGYU0C8 gc~9ڠSh5GNzMn.Qj`GFNOeHnR|Ew_=*~*ԝR'?F.Ί'n_zV2ԻB :jOXe2ҶpᱍØn`OIy&CL'olg!/Z \bjB5mU둺ު.:U^c_`x%)&z/.ǩ,7[>߯^ff!<-<.Vਐ'kRk&rR8#)0}642?C J)zp"E1};I\ӓkĸj? k=9Yz<\g\c'5aUfp.LRY]QpGZ̨$K+η8hcf ёّZUҦN.Ǡf6|_8NPP1\q,o碔{T\{wd-P=G`96G噯2[:L<o^;pqbO`v_zq/29 #0W,ߔZܱR5#3Q= mÛSMBPL՘:*i<^n9"Z%Q4!d*-p^\b=Yt!L\*K`A~cfbGF,Q7UKX\D6H7@;~sklHUv4^ y~ ?gGFɝf6L,4_g!.7qKZl%a&[<ɝʇE;~QK^/Ifz>iS=zVN:{L+tX2 ŀcr"Օ "D>ˍyjQJB(oJZ`v[bY Ƭc#ơ @vDNnsVV̺ ҫn4.h6)9˺V.MMw1 <ܮ3|\hF8e0 4viXK%8q<-Q XnKOOhcEOW-IF\Zoe~8erBi#kq4}VhAorQ4HX|!CoY(\-U C[~o VO,C'jK=#|Vl_Ql" D&cLC{pG_Ca/_e(Ǹ8\*qv唧Zg`V85Ud=6M9jMqDcq籚LgLd6TvHJv;:3;I6z˪ ıHTd%(` ,WYn#g_ k.ݦ@}bMR BÇe`, sqi3mrv)7˖Yn& 27XC.! ?zVZ|&Qffq>o5bs'34*ilm܂;~^L*b;hr|~@Kv iSYu~&!oy-d?W,hņtMRrV\XE}B*3 . 5j|Nk *,Xl 2#ӒwDN-Wgu'V'葓*c6B ۞`$?W-V9}Tӭde\Y-%Pgb~aMMz|:`!QCQby%V$quYYvL{Jٛ^_w@rr>ߔ۹sv26ԋ9Hep5w50*inݣg䬙x2_] .M7.vZi鎣Ԝ A ߃*2\ζ6NY씓y&Dkjt]Z]Vvxd~,豢Y+6I 'rXF[\-PrWSʊ0xz}Ji4unp<ӄa^X0>1jO;D3 6x"gA¯Tm>^L:=ZɫӒЃbU~ fe)j&k3nkPJElG/ULlњuV7/κ p|o޵?НGWksL""Ip0?ǟ-W`7Ǭ.5pV}SSL[ĝb7wa>z`xCEBELPTT߬wlWؚ:*a);l;m9}ϯ}A$K&,;81s_wI<}̥3Q-J[ZLbR/&8Ep8b6`Fל:](2KP遍Μ>X.U&f-q[q p )()fXr{RWl=Wjbp,G ] ]چʶ-;Mw K,w5Jo !qfk:v5g4XEÎu,=_U!ZqeOxs]ER` J* Vۻ +illszK7P|7P yd=WzTܥ,sfxH11{J3 -ˏˇ8voԞ 0XUPY;GL2D| 兏X%zMm`7}*W%Fj4 Tb3$-{';*Ro*-jS˯^_֚w`Yݱ8˔SS?Qy+SDzӿP+4}HGEJXp=Ҭ6-M˕pD郋}rhkMZ9H%%YT!(sWXF`YH^^ZzR C2;[!Qg&z!2kxWOv)dA@y2w .\ܹ瓨cw@=qΫ}ceFO#z?_Z2m)mHT3G.p )ER\@kqqe%S,p KlΪj}>/?<5px#VNe(8zJ$ij69ȂXL'9Y|R\Lj x{RIfdci_那R T5^0R՚%ݔ_%e\q~,~*R\SToh&Q\SL돨lbP+K[WuM$ڼD6=7.#_ !Rlrkض&Cg_IT9G~0f[ )I$8!XYo1 7sJUgӑ²bGq=@UdeYyo"ɺ8]e>:G:+Iu~C>/o k׈SW=Nq@FjԎJ*ɴ5XWT?k-%2lVZTf@.Ωd[u:80TjU @c1<%xi5q&$7!ׁPY&q[E1jeJn$y-3(qUC_(.OyhuaYGzEq&fдcJSeal(^dDt}|ʍ<:vݮ{~󜹪Mv6 ⸷:H', dKd^Ld!kدP</|ѓFۗ}ʕ \ #|-3D28JE=` endstream endobj 179 0 obj <>stream hdV TSW}PkC{Qh*?B"P@O_EX[+ ZbЪTE-:BTV8:eNXtY7uNι|#\c"&͈1,̸26 rXI!jdǫ`SܗqL2gZRWh$ +=8i7Jf4LٹY+LiYکfKْdՆ-_%e2YVRmiJӊmJ6A’`4%XReژt 6l6!8lѦP߬lCV1%bg.0P2 gș<C3D0sT*KtT9y9;y/yi~tEy΋4pFz|WA \.?Ӆ,0Zjeѓ`&D~zj=eoS]_]:cB}uIU;ʦegӨ&C k#茡j08{C:*xK^qlfOo~q0:fqV[6 %iS=@|ԕJ,sn-7*$wk07#p g0E$v*~~j ; 7lq^Ԓ3Ⳗt?^%Vgp|, 3q2\ǔM>em7*u5G[돥K]'@&qߛj~:.{O=Gf~$_hmޛhc}[GS߾7c>/uzyG̙[o%ٲ{ >9vc! z ^xZ8oj./o$Xb*nҀCX$Xb7F?ic,FSs{ý4`[ !W``Audt 4o(%/k~iowK6\ `-^#@ j_e5&+|U&8sTu:3g0LCTZX g8J5W!nCOnb&o@ঢg/R!6@w:Xxb4,!YinQ hs H4nVʢk'6OX!6Jt֊,RG)19 8c(>b>A}|\D#9xU-KBexod+CRp<=2(/a$аe{ujE>{Ou/&@] f*>m0eTq!Ղ]wb^'bӶ-*;V~MLJtRڥ80A #mrlĐ?D!Ҋ}.hoc?HstIiM;DR\F"3>K%#»ߝ, ^m+)MMt^.*}HScJ|O?zV rhk٩kgc26f wn/5:}S5|qmv%k?lU=nZL ӮS;Kw(UbYD ,E˕ʮ.֊d% "_|mB(}a!=gh)%iq{9A/?WP{lQI.{{$YRS(δ>1ǨAvӃy("ok1!͠'ܵGhd.H#FpUN>jK﮲4f&tO#tf@R8:ee4=R{R"hE@RR~y.dK@4k (V \[j2j`qJsࢿ5qqI._Q+ۍuۦyl"q\8q;x9 k9Oid !b'`.f/OaSO%:ٿclf..) YɹB7.RpnQbA֪k'd_83uoJor]E701Ew>%g82>stream htWyTSgȽEuz)ܫƺ׽jjVQQD= I$$@d #`Em݊eSǪt:~]ڙsf99qḹr\\\#)~􀔄镹N9wz Eym+9W-;墔d bi\2ZMVL?7~lϊM% b_f\(;K#I_%lOOM  ")/ $A,H bQL|BF(M(H̒ȳb2Wg)wXqJ|J(%A?xp\pfp</ǕЕԕwlpv80~ԅe~hzK\\X0C:swkLpix\7%R_:=,ᬇ+=*=>'oyy=?3[FV qӛ䈨3EJR# @Y*l/hs t 22D޼&&_"<~ފŝ[1>̀5N=2-@;7Ovx ?e V걨yE-0!_Z<$E:4,p:0ڨF0yܫfiJTF5)u~d`߹"IP#p0u6y" tXkGO؟j8hSpyh;w ދ8ZbJljH@9+SRé׎Sri`Sw}JXX?|sx{ж"3x' P&\XF.GR҂̬Sw!`%ڻȫែDF=@/oO_$"Na C":ZD1VA?_*G.;&xk_ӛ=8zAML]m$YID+*$a{ Lɞy}rףmCtY:Eh_ķa`ߛ'>[HOGgVSK ?u3|Xv [3EtV>'iMvZ3D_4'!kQe+782cG |kyV]N_lZU̬2J8aQVB wj XU/GQ7^ cRP_T) lI!9څ(EutQ`E܏1Uħ'jm;-[nt і[d`d #F!n߁!}6n;nhg+Vb78Meeދlѣ)fď8Uc4(FOROұC4su,/k6unkS=X91 ~3 (Q <@6ZlMrJM'gj I.נObXCyc.OmND^`-XYa/o͹ESCX= %agZa ؂YhE2k1qz CwA1B^&X X̞a}1T$4zim~1?4u&S(} 1D\=X6F1wUe6) \OlGǴ#l1|g3bH 4Z %+26Iڲ}V5h ӓzkH1]({y?K=@f}Ǐ`x7E^ԪZ[Owt7fG>Vv6uOv%A \G$2P[^;#[}˿։Yt4ZW\4zmuc_]_Q' ZF]h!նFN4')W|gs4vEX!#~%"L'sk 4Ԝ ȥ5PY}1TSսFccQ3%SaDhX<)~6[zmT$M=ӠWDNbSrHEѿ|>\j,f tՖW1MG~xHO. ´\hcj@S/9$iO{kbK 5?! aW h>>Z\FPBE}J?>>ɡkM mfGsE]W14}VrxdBizw߉:0270(l|r,M! d.;֖bX)D%g%RJkmö񂜀єTmaߍЂPCT3L&{+FQ'yC[pl3'>ɞ&^YX;qTL=}9 nK)Uytpe<t0 iҗR0z;p!KG֢m>#eUFeg;GX^IUIUVןbNj=٩lOt> yuȅNKLVUd4 ;h\f[z}!̓(4(MRİfٲD)%ӵ: LQk ̭'Mw>YhZN4ԷTD0cy)Jkaq:Zjuv.xL 1aL:.%_wdP2B3lwa߽_֖(TKUXDEe˿Vj~A\9d`1nLq+4Xeuoާ. vIJHkj2_i,(5IE_sJ4MG\| ̲ endstream endobj 174 0 obj <>stream htV TSgN 1*E ^dST @TT2uցFUYZVVzŋV*217zf3g$s{La#âbgNYm%^.W3o;uv2:,3+ߔdiZ?_oW3YW?6$5`gӳ)L>ǘ:YYB;![k2fMy:ø"Ϙצek>՘7-f.Fedg!ӵTL6fR4c ӏlJ6V&o#(22O,T)bdq YLCӗ)dL+,)[/uKlٸlb;6Ӷ-W$(QQt1n$JRKz@vrOUS^Rv8(}A+T}>O 닄$5cU(8 -=Lkˍs|1L_.I_4?s ^Y# ]jpJ嘌ɩ8.dH>IPqH&o @.V-0 ^>'c"qȠBtzUm8Mv}Q//xU4xqh#CQGmP{vM=ӛخ3w%챲S?jGcG:M M{FfM_^q*Q%UC0:^z;l.cp'ȕM#*rp"# !E̩Cu^w : =nO6FXΔ^ΨH8_,FhDtÕƂ*=5e(Oq,PC A}*j4A*xC 0gXK}9$0]:kh,^aY~:ɏ 'S}IgfB`3 %dZp xY pAggWi%:U]+QP`qc&^0(@QSB yB7iYY8RեHrK>Q}7 7JդsTA]tӁ5A6]~~M v 4}C9O~K9Wyte@*b@!plZlV)+0xI*PgP*1|bRpWhw7T̽uh85?\\+7fN &&CC8w<=U3#QeȌYW⅌td_7D\[DiFmQȟW]R,гϞ~>{(ܵR_K$s6z t4o%EM;90'YL{2TfջNqRqoIk ,|LX'?}RZz.RZ)^e?  t-#盈Ëh\D@_dKOm@^J8J،Oi9b̆&c ")`lKQ10F Zw{GCCgp;jX폏yq}v:Jh<3_|ʣqx=ôs+oKډeq#`41SPZXA%/aL_i_@.JC]у;w|*4~\vݻroSiVJ -dc+6l.aW)^{_(z޴$tJ EG<`o#n*ecJQy .3 f lj>yAuR?wҋA=K՜H)zXC| t4XpvtIBUxwDs/fDjg̎I:[(#P!ߊZV|08b##u^:a/#"Vxn>G[e %dM%kה߁˔\Z="% $CRЊX'q{׀ƻE6[¯&fp SHTi%= Sx*nkPOLvJжuؖ/+P6|Co/l~p}t C~Zlh;{z<-,W<@wqu`&T3]HՌ5>stream hlV{TT?d;gRI!>R@D@4uPx 3 *;##2z,k+3s׺; χQ(BdxX_MʎӤƤƆEj%k3_U >8~]۳gA}6g|[3 ZUGDžL]!5d:4)}Y:֠LNթ-Ofk3ƨաk֨ctd]6R*:FNTgjS+ԑLCF:t:1-tZCtYt$MV'0 ja1`_f b1 3և`&1L&eb} f8 f3a~T*Jw|;{of-n('sHLy7[ Loޮ#%(q# Q53b?=.>l}+hs$YffvAoV=,vJ>.WJ uܾlYXb]!a3P *O9{(CO4 7-kw2sBd#i_^09XuH)! 7|C.m*{i#=>5Kdx={!Yl6RRRFx3A0"oC?[dgSׄ*|`聮=}|pD^2xt.N]E02UP s_V=)kY^,Bo(q}Od)^<9Xh-Xb!*]U NB28+vEɥ/*EB;x<wPۛMWʨ=fqT%CФe`6&Hګ+h.=9_Դa7y4Kn%Wnv\`x0ۡ?te{Eb,vqCY @e+(Q(pcCmcqZX@AFdMӋh,nYpyv6ϱ6.$)v(|Koך+?01$jF0 9?}[=~!NF=f4}%e6ʆjs谒§HیuWxX]f/]KNǁ} ~(p  BdER^T+ַvG!^hL1wuqnHAUPRjnI a{ ?)$ B(yw,=\(3]cjXFt%|/M`yT-b&׊+&(NBCw %=v䗮q!Nq ^̮{q>-iBx uE6{6r3zu:H$T쎍;Ԃl1=&󐭍]|d+l8݇--tڅmâ''i'w :Ƹ'G\c:] e쯌0%$ȦDrrn1 l.3<3úl #dbM*u׷m/Aug_r|"\~ұ|3tgwS:*s ä;0"|vNlkܽ\msCE#$6F.oCټvmtNQ`?{IbDV_ {~׻N*98eܽJ4Jᇐ$sG8T;Dw?\^ugaHyLsT!̹j/_szMl(E۹8V£$²:Tvdqҳ֢m.o 9ל[s[JxO+^JI;ML'=7>9v+?3 B5/#N>de>dP;JP^;^tp`tYI-* O+`@.wH04o?dNXhh0AKMN>'uSser4.PFP?ic02e( s;/g"2lMڒaŁXБ['&WzdHJ8&'էO. T4빙)kjr7IgS.E&Yc/)pOmLLdk9e@V5tL ¡3dƦެ4$ QOE pNGI Pz3PC4aqm4MYx)(m%< A@BG;^ őW"my `=ԾMu^CA9nǺLS2[qFkeY -w?)K{w=Qwu ceU\@l%0,vp*Cc>aCo)b'ot{?TSqvIQqyb=LZ ?:LyEExիKgH2BQ;e찱eeU$=waO l3FCo3ެ;USvCu> ޒ'vSF2\~FElE**<ϫpLDc"IZ%Hbv_˻νtGĹbrIA82؜]wW-oZ.s1bM0K:j; I0HzpV8|Y̺SX#7vu>stream htS}P=]4]]=gwE ?LEC;icq0I84˯q,?F3u4GmJ1fz{kjk7y~$I-K2VIoʓK (v(TDjSLW3¶q^䞩ϢImY*W(R.qf,1ѼL#hNrC̭Q]*,*YxQLsF*bCu(tNġ*Db;6\7RvT9Ĵ墭>WVDISU.ɡGAF"qe$D,I&H]>NP\b-$crYL Lißa`Wy p<^m(#6zAh@+<"`̈́s(XFuq8ÊӲ16Mzt1Sq,N&4sU;¶~tTavY)p [{!҆Sĵ9d*w,7 cu%['Z*u 2sq'eFG3 X< @G10Ka#oSK޸fd/OL FEZ endstream endobj 187 0 obj <>stream hތUiTWAc.",ґEAAeY4.AfPQ1q93qD4 J[xysf̏9Uԩ{*FmèT*ǘ q1^ae&b_Blhe]1LdTa1 `a*Ֆb_W1 bL&FLefAS2jg?Ua?h96'lm^ۺ.QQ߲ٕlMs%\5wwi_/TM漦Ey6„'p&77+;{4aZ?]CwB EvZII48TLps5qz̚61/R#U+CƓϔi޴ 0H|}HZX8n~9MF.KH4%M0VAKd_ZӤ{ߋhnl)e}J}۽ 9ɧ{5CΌ2ͼ<^V^[N"h޵;x?A!:}M4r ְpMQTֱUǪԋav"Z~UAuh+Cm8ðA05Qh/t KHѓ`'R/ՙh 8eC.gnjKH_间ΑM* nOyK"Npy&X As}a"&M10 n>͑uJZmOeAԢBNCpl=4 y 뒗ҌL 1 Üp):b+ȅz17`pQ%AZYW鞶ஃZ-xU1ՈlN{+C{4"ɻ"xFm'rU< ah&V*0v/j-zpBEȸxzyMRL.e=+pڜ@Q`kOT'$yk ڐkwGt#X.G;~0]jecCzl.>j6 AH#[@?=v"fjsP(>,^B#eOvK2}2m4WR/J+;>0U0x2@Cϊoڭ6'|lRO/8^ySEIuqxx€]+]ڊ/}@l/dyZ.ZKor4 Ei{g  K @߬KGD@pn]wMg&L58\H5B z!: ty׾GTЎI]IaHSS\лrn붘"UpVz WҐ,@\~+47a[]H$qV* |B͹S:9e[_QPux[nV/C>D[rC:ƿ7u~s+ث^؟QY31$74@ku(A¥@1<۟hb7πHD0SmA)_!Ϊ_$'->"Uϋ#NHHI{snଓKJ _GxG uwC"6Ҟf6"ci]Jl# '7=,?pr)uoju 𯗿B簸R IOM%Sswrp.@ ~8Bh0 ?K &m2286ڏw0>:ZRxD(@S0L,30F"hV 0[YDBn iDƎ&8Zߢ>~%E†9br*Y 8ܔܤ8C/߻pC` wo˹g3A =;uTPG)gI."9ġ^c)%Mx9׍X%m`\q8Dj$lر+g$țI+,dz*߱W(,&Z'9]W> endobj 41 0 obj <>stream x[ks۶+w əNflık9mڌ?eÑg)ʒILV:Q(bOJa$H$(! I d" Q"HHI2P yPA"~$=-e |ů??LKtx0B(?[J 1 (z!Z>$~$B=Ɗ:1BB!$8\A,D}F$ΉQy"D@JtG,##b (Cx%%OpC1h'F,xw/T T3}E T"TGCxRx|(DZq>`Bܒ\O.(+ A\-=5pP^I=+uo7)4iw2Voi6Jg'QoL;I?_ҟxs+q2t6^3p<\tӹ@ۻNӻmsǝhnם)^J-zeƏ{ƝH6dƔ|V) n}s3g\fkrְ(Qgn 4d Uxt^Љo7?iSAĦLbӛɶD8eעKv7t%?2ו*8 5'ߋd/|QQ[_T1Zʩ+J?"v:kS7~M"K~Nf?.搫;OG͆)de]nq'S.gBu7Jva?OA' yňGl(&av92vQ"lgA ?\*HNtNj2Wd&^!zPyaCB((H@$#Deê"Pa`;k`cL?lVՉ.=G`' t+L~I@&N_k?+?kz9yЄ:dJ%3ٯ톆?Z0Y@`K5 -Oԋ`)7UfaJ>E_Q:+˕lo(;zQeCwʆ-f8nB*xP߉0mdo 䕷D=vlI$F)qŎ'|m'n,7=׸!W;B*ϴ 96/*sl&fkь.*(5WRk2JBřX˒jR5 CќRRFCIaovEh3mMΩOc:[{:wtC%tJ.&Q#]\cک6,{&U*ӁMf%(fW' elZ:-i,N(Z&al$. T>3T̜g=v`c9or´ahz}-6Se&?R~,yپM/rX9 æ`KkTMX4%h_* 'RQ"Oh\ ,Eeǟӏ6c%`đSOXr"g>*V`ši{yʗxf)&< e4OҌ朴+)肮#0^۫)3H=mӀ湌4Mi}JLǐnijNL3ݤlҧ?_Mew.2h~B).wq\lA ] އ1whx'vy+~;޼ƸjcѪo* l|60o,[0طZ>:puN?g)(m핏ShPHnWgȎa)=g) QJ4`Qi0MΡ [J߁lPѰ16$gBFpլUU{ Ve1yVhfǐ(G/RMc#dKi]ɦ 2!%H| \_񒸮aҀݢ#7&R]DEF_ێb2n֡ق{rUVԓ|DrՖ=P p26NNN~7o0_ٌnX"NSGYMWVEUP 34|Zg{Wob*mڳZÂR L-"jBE~" 9zg;uGذ>o ~Lű:.l_8k7SCլO o+[M:_; endstream endobj 189 0 obj <<7d029cd0cd378d10dd05c9b2095da195>]/Root 159 0 R/Length 581/Size 190>>stream x-[Ha?lGun榫`.ي@p!EePW!yQAtS`D҅]QFT" Eŏ?ƷwJ)Ur)eS*!hA_Yq# ap*/t؜q?L5?`UyhmS09 oa1]g6%`E(mm3aq9;M`!zSO ABӧ\^п*ZotAh3JIPu>y,kh5*)ӝ$MPv;KdpP'n-졆 NXԹIkDnŐzi)YE+|[=K뎏~crJo4(lt4ZqWעs1;u^