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[(tached)-223.3(to)-215.4(an)-222.2(air-driven)-220.9(Cell)-214.2(Tram)-221.1(\(NARISHIGE,)-221.5(Japan\).)-225.3(The)]TJ T* [(tip)-228.2(of)-226.8(the)-229.2(needle)-229.1(was)-229.8(inserted)-230(into)-229.3(the)-229.2(circulation)-229.2(of)-226.8(zebra辳h)]TJ 0 -1.1174 TD [(under)-300.4(a)-301.8(dissecting)-301.3(stereomicroscope)-312.5(and)-298.2(the)-298.3(pulse)-300.3(time)-300.8(was)]TJ 0 -1.1116 TD [(controlled)-295.9(to)-296.1(deliver)-292.5(10)-295.9(nL)-291.4(of)-290.2(the)-298.3(drug)-292.4(solution)-291.2(into)-292.6(the)-292.6(cir-)]TJ T* [(culation)-311(through)-307.3(the)-304.1(glass)-305.9(capillary.)-310.9(Injected)-306.3(zebra辳h)-311.4(were)]TJ 0 -1.1174 TD [(transferred)-217(to)-209.7(six-well)-206.8(plates,)-214(30)-209.5(zebra辳h)-207.7(per)-211.8(well)-208.3(with)-212.9(3)-168.1(m)0(L)]TJ 0 -1.1116 TD [(of)-209.5(辳h)-210.3(water)-216.2(for)-210.6(a)-209.6(treatment)-210.8(period)-209.5(of)-209.5(24)-169.2(h.)-211.9(Zebra辳h)-207.8(injected)]TJ T* [(with)-282(10)-272.9(nL)-279.9(0.9%)-272.7(sodium)-278.5(chloride)-282.1(served)-279.4(as)-279.6(vehicle)-276.4(controls)]TJ T* [(and)-246.4(untreated)-244(zebra辳h)-242.3(were)-243.7(used)-241.5(to)-238.5(con農m)-245(that)-242(the)-240.7(vehicle)]TJ 0 -1.1174 TD [(solvent)-285.4(did)-279.9(not)-279.9(have)-283.2(an)-279.8(adverse)-281.7(effect)-286.6(on)-278.7(the)-281.1(zebra辳h.)]TJ 7.3823 0 0 6.5614 278.9857 565.1148 Tm (24)Tj /F11 1 Tf 8.9663 0 0 8.9663 59.7543 536.9951 Tm [(Assessment)-311.6(effects)-309.3(of)-311.4(drugs)-312.1(on)-312.3(zebra辳h)-309.2(heart)-309.8(failure)]TJ /F5 1 Tf 9.843 0 0 9.843 69.7323 520.5542 Tm [(To)-400.8(assess)-405.6(effects)-402.7(of)-405.3(the)-402(tested)-400.7(drugs)-402.7(on)-399.6(heart)-405.3(failure)-401.9(in)]TJ -1.0137 -1.1116 TD [(zebra辳h,)-240(eight)-237.3(known)-236.8(human)-238.3(heart)-232.6(failure)-240.6(therapeutic)-241.8(drugs)]TJ 0 -1.1174 TD [(\(LCZ696,)-314(digoxin,)-310.9(irbesartan,)-317.4(metoprolol,)-311(qiliqiangxin)-314.5(cap-)]TJ 0 -1.1116 TD [(sule,)-337.2(enalapril,)-339.7(shenmai)-339.5(injection,)-338.7(and)-332.8(hydrochlorothiazide\))]TJ T* [(were)-456.8(selected)-451.3(for)-452.5(validation)-457.4(of)-445.7(the)-453.8(zebra辳h)-455.4(heart)-451.4(failure)]TJ 0 -1.1174 TD [(model.)-334(Thirty)-336.3(AB)-332.4(strain)-336.1(zebra辳h)-334.5(at)-331.8(2)-335.2(dpf)-331.6(were)-335.9(distributed)]TJ 0 -1.1116 TD [(into)-183.2(six-we)-8.5(ll)-181(plates)-187.5(in)-180.9(3)-168.1(m)0(L)-183.2(o)0(f)-186.5(fresh)-185(辳h)-181.5(water.)-185(Zebra辳h)-190.5(were)]TJ T* [(pretreated)-298.1(with)-287.8(a)-290.2(test)-287.9(drug)-292.4(for)-285.5(4)-168.1(h)-289.1(at)-285.7(serial)-296.9(concentrations)-290.9(or)]TJ T* [(dosages,)-272.3(as)-262.4(indicated)-273(in)-261.5(Table)-268.3(1,)-263.7(followed)-270.3(by)-261.4(treatment)-274.2(with)]TJ 0 -1.1174 TD [(verapamil)-251(for)-245.1(another)-246.3(30)-163.5(min.)-244.2(Zebra辳h)-248.1(treated)-247.6(with)-247.4(200)]TJ /F6 1 Tf 22.8545 0 TD (l)Tj /F5 1 Tf .5529 0 TD (M)Tj -23.4074 -1.1116 TD [(verapamil)-354.7(for)-348.8(30)-169.2(min)-344.5(were)-353.1(used)-351(as)-348.7(the)-350.2(heart)-347.8(failure)-355.8(model.)]TJ T* [(Zebra辳h)-242.3(treated)-236.1(with)-235.9(0.1%)-232.4(DMSO)-237.3(or)-232.6(0.9%)-238.2(sodium)-232.4(chloride)]TJ 0 -1.1174 TD [(were)-249.5(used)-241.5(as)-245.1(vehicle)-241.8(controls.)-243.8(Untreated)-250.7(zebra辳h)-242.3(were)-249.5(used)]TJ 0 -1.1116 TD [(to)-342.1(con農m)-337.1(that)-339.9(the)-338.7(vehic)-8(le)-337.5(solvent)-337.2(did)-343.3(not)-337.5(have)-340.8(an)-337.4(adverse)]TJ T* [(effect)-396.1(on)-388.1(zebra辳h.)-389.7(After)-393.5(treatment,)-392.8(zebra辳h)-392.1(heart)-388.1(failure)]TJ 0 -1.1174 TD [(was)-287.4(quanti辝d)-283(using)-276.1(a)-284.5(method)-279.8(as)-279.6(described)-289.8(above.)]TJ /F11 1 Tf 8.9663 0 0 8.9663 59.7543 332.3905 Tm [(Statistical)-336.1(analyses)]TJ /F5 1 Tf 9.843 0 0 9.843 69.7323 315.9495 Tm [(One-way)-184.5(ANOVA,)-186.1(followed)-183.9(by)-180.7(Dunnett誷)-184.8(test,)-181.9(was)-183.7(used)-178.2(to)]TJ -1.0137 -1.1116 TD [(compare)-369.5(differences)-373.7(among)-365(groups.)-366.9(All)-367.3(statistical)-373.1(analyses)]TJ T* [(were)-255.2(performed)-255.3(using)-247.3(the)-252.3(SPSS)-251.4(16.0)-248.6(software)-253.8(\(SPSS,)-250.2(USA\),)]TJ 0 -1.1174 TD (and)Tj /F7 1 Tf 2.0217 0 TD (p)Tj /F8 1 Tf .6624 0 TD (<)Tj /F5 1 Tf .72 0 TD [(0.05)-571.2(was)-569.6(considered)-573.1(statistically)-577(signi辌ant.)-569.7(For)]TJ -3.404 -1.1116 TD [(quantitative)-305.3(analysis,)-308.2(all)-298.5(data)-300.6(are)-305.1(presented)-307.1(as)-296.9(mean)]TJ /F8 1 Tf 21.2706 0 TD ()Tj /F5 1 Tf .72 0 TD (SEM,)Tj -21.9906 -1.1116 TD [(and)-252.1(results)-250.6(were)-249.5(statistically)-254.5(compared)-249.6(between)-254.1(drug-treated)]TJ 0 -1.1174 TD 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[(rapamil)-288(for)-279.7(30)-169.2(min)-281.1(and)-286.7(1)-168.1(h)-283.3(induced)-286.6(severe)-286.3(heart)-284.4(failure)-286.7(with)]TJ 0 -1.1116 TD [(obvious)-341.7(cardiovascular)-349.5(toxicity,)-348(and)-344.3(the)-344.4(heart)-347.8(failure)-344.3(could)]TJ T* [(not)-400.9(be)-400.8(rescued)-408.4(with)-403(digoxin)-405.4(pretreatment.)-408.8(In)-399.6(addition,)-405.5(the)]TJ T* [(heartbeat)-331.6(rate)-329.4(was)-333.4(\(183)]TJ /F8 1 Tf 9.7339 0 TD ()Tj /F5 1 Tf .72 0 TD [(5.8\)/min)-329.4(in)-330.6(untreated)-330.4(control)-331.6(zeb-)]TJ -10.4539 -1.1174 TD [(ra辳h)-351.9(and)-350(\(126)]TJ /F8 1 Tf 6.3702 0 TD ()Tj /F5 1 Tf .7142 0 TD [(5.3\)/min)-352.4(in)-353.7(zebra辳h)-351.7(treated)-357(with)-351.1(200)]TJ /F6 1 Tf 15.7701 0 TD (l)Tj /F5 1 Tf .5529 0 TD (M)Tj -23.4074 -1.1116 TD [(verapamil)-464.1(for)-464(30)-163.5(min,)-463.1(indicating)-463.1(that)-466.6(verapamil)-464.1(treatment)]TJ T* 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[(T)15(o)-196.9(de)13.9(te)19.6(rm)19.6(in)20.7(e)-198.1(w)0(h)20(e)0(t)19.6(h)0(e)19.7(r)-196.9(th)20.7(e)-198.1(z)0(e)18.5(b)0(r)15.1(a)0()19.8(s)0(h)-186.3(r)0(e)19.7(s)0(p)21(o)0(n)20.8(s)0(e)-193.2(t)0(o)-186.6(h)0(e)19.7(a)0(r)19.7(t)-197.1(fa)19.7(il)20.6(ur)15.1(e)]TJ -1.0137 -1.1174 TD [(th)20.7(er)19.7(ap)19.7(eu)19.7(ti)20.6(cs)-343(is)-336.2(si)15.1(m)15(i)0(l)14.8(a)0(r)-337.4(t)0(o)-336.4(t)0(h)15(e)-347.8(re)19.7(sp)21(on)20.8(se)-343(of)-336.2(ma)18.4(mm)18.4(al)19.5(ia)19.6(n)-346.7(m)0(o)19.6(d)0(e)19.7(l)]TJ 0 -1.1116 TD [(sy)21(st)20.9(em)18.5(s,)-384.5(we)-384.4(pr)20.9(et)19.5(re)13.9(at)19.5(ed)-383.5(th)20.7(e)-393.9(z)0(e)18.5(b)0(r)20.9(a)0()19.8(s)0(h)-382.1(w)0(i)14.1(t)0(h)-382.5(e)0(a)18.5(c)0(h)-383.5(o)0(f)-382.3(t)0(h)20.7(e)-393.9(ei)19.5(gh)20.8(t)]TJ T* [(kn)20.8(ow)20(n)-329.4(d)0(r)20.9(u)0(g)15.1(s)-329.2(\(L)19.7(CZ)18.6(69)20.8(6,)-321.3(di)20.7(go)20.8(xi)20.7(n,)-321.3(ir)20.7(be)19.7(sa)14.1(rt)20.7(an)19.7(,)-331.7(m)0(e)18.4(t)0(o)20.7(p)0(r)20.9(o)0(l)20.7(o)0(l)20.7(,)-331.7(qi)20.7(li)20.6(-)]TJ T* [(qi)20.7(an)19.7(gx)20.8(in)-486.1(ca)18.5(ps)21(ul)14.9(e,)-483.7(en)19.7(al)19.5(ap)19.7(ri)20.7(l,)-488.5(sh)21(en)19.7(ma)18.4(i)-496.6(i)0(n)20.7(j)0(e)19.5(c)0(t)19.5(i)0(o)15(n)0(,)-482.6(a)0(n)19.7(d)-496.4(hy)20.8(dr)20.9(o-)]TJ 0 -1.1174 TD [(ch)19.7(lo)20.7(ro)20.9(th)20.7(ia)19.5(zi)13.8(de)19.7(\))-254.5(f)0(o)20.9(r)-260.3(4)-156.6(h)0(,)-246.4(a)0(n)19.7(d)-260.3(th)20.7(en)-245.3(in)20.7(cu)19.7(ba)13.9(te)19.5(d)-254.5(t)0(h)20.7(e)0(m)-252.3(w)0(i)19.8(t)0(h)-244.2(2)0(0)20.8(0)]TJ /F6 1 Tf 22.8603 0 TD (l)Tj /F5 1 Tf .5472 0 TD (M)Tj -23.4074 -1.1116 TD [(ve)19.7(ra)19.7(pa)19.7(mi)19.5(l)-300.7(f)0(o)15.1(r)-300.6(30)-146.2(mi)19.5(n.)-292.5(Si)20.9(x)-306.4(t)0(o)-290.3(1)0(2)-295.9(c)0(o)19.7(n)0(c)19.7(e)0(n)19.7(t)0(r)20.7(a)0(t)19.6(i)0(o)20.7(n)0(s)-295.7(o)0(r)-290.1(d)0(o)15.1(s)0(a)19.9(g)0(e)19.7(s)-300.4(of)]TJ T* [(ei)19.5(gh)20.8(t)-231.6(k)0(n)20.8(o)0(w)20(n)-225.7(dr)15.1(ug)20.8(s)-225.5(w)0(e)18.8(r)0(e)-222.2(a)0(s)19.9(s)0(e)19.9(s)0(s)15.5(e)0(d)-216.5(f)0(o)20.9(r)-231.4(ea)18.5(ch)-222.2(dr)20.9(ug)-215.3(\(T)13.9(ab)19.7(le)-216.6(1\))20.9(.)-228.1(T)0(h)13.9(e)]TJ 0 -1.1174 TD .0074 Tc [(NO)-6.1(AE)-6.4(L)-328.9(w)-.3(a)-6.4(s)-327.6(2.)-7.5(5)]TJ /F6 1 Tf 7.1132 0 TD 0 Tc (l)Tj /F5 1 Tf .5644 0 TD .0075 Tc [(g.)-7.4(mL)]TJ /F8 1 Tf 7.3823 0 0 6.5614 407.9054 389.7637 Tm 0 Tc (-)Tj /F5 1 Tf .5683 0 TD (1)Tj 9.843 0 0 9.843 419.1306 385.3983 Tm .012 Tc [(f)5.2(o)-.6(r)-323.1(L)4(CZ69)5.1(6,)-325.5(1)5.1(0)]TJ /F6 1 Tf 6.7504 0 TD 0 Tc (l)Tj /F5 1 Tf .5587 0 TD .0095 Tc (g.mL)Tj /F8 1 Tf 7.3823 0 0 6.5614 512.6172 389.7637 Tm 0 Tc (-)Tj /F5 1 Tf .5683 0 TD (1)Tj 9.843 0 0 9.843 523.7857 385.3983 Tm .0126 Tc [(fo)5.7(r)-322.5(d)0(i)5.6(-)]TJ -21.6335 -1.1116 TD 0 Tc [(goxin,)-204.9(10)]TJ /F6 1 Tf 3.9051 0 TD (l)Tj /F5 1 Tf .5529 0 TD (g.mL)Tj /F8 1 Tf 7.3823 0 0 6.5614 375.8739 378.8219 Tm (-)Tj /F5 1 Tf .5606 0 TD (1)Tj 9.843 0 0 9.843 385.6818 374.4566 Tm [(for)-199.1(irbesa)-8.8(rtan,)-210.7(10)]TJ /F6 1 Tf 6.9577 0 TD (l)Tj /F5 1 Tf .5529 0 TD (g.mL)Tj /F8 1 Tf 7.3823 0 0 6.5614 480.7558 378.8219 Tm (-)Tj /F5 1 Tf .5529 0 TD (1)Tj 9.843 0 0 9.843 490.507 374.4566 Tm [(for)-204.8(metop)-8(rolol,)]TJ -18.2525 -1.1116 TD (250)Tj /F6 1 Tf 1.6703 0 TD (l)Tj /F5 1 Tf .5529 0 TD (g.mL)Tj /F8 1 Tf 7.3823 0 0 6.5614 353.8771 367.8802 Tm (-)Tj /F5 1 Tf .5529 0 TD (1)Tj 9.843 0 0 9.843 365.2723 363.5149 Tm [(for)-371.9(qiliqi)-7.1(angxin)-376.5(capsul)-8.9(e,)-368.6(250)]TJ /F6 1 Tf 12.0781 0 TD (l)Tj /F5 1 Tf .5529 0 TD (g.mL)Tj /F8 1 Tf 7.3823 0 0 6.5614 510.7463 367.8802 Tm (-)Tj /F5 1 Tf .5606 0 TD (1)Tj 9.843 0 0 9.843 522.1983 363.5149 Tm [(for)-366.1(en-)]TJ -21.4722 -1.1174 TD [(alapri)-9.2(l,)-298.4(10)-169.2(ng)-295.9(for)-297(shenm)-7.7(ai)-303(inject)-9.3(ion,)-294.8(and)-304(50)]TJ /F6 1 Tf 17.6996 0 TD (l)Tj /F5 1 Tf .5529 0 TD (g.mL)Tj /F8 1 Tf 7.3823 0 0 6.5614 511.6534 356.9385 Tm (-)Tj /F5 1 Tf .5529 0 TD (1)Tj 9.843 0 0 9.843 522.3684 352.5164 Tm [(for)-297(hy-)]TJ -21.4895 -1.1116 TD [(drochl)-7.9(orothi)-6.8(azide)-9.1(,)-279.9(respec)-9.9(tively)-8.2(.)]TJ 1.0137 -1.1116 TD [(As)-411.8(expected,)-420.2(after)-416.8(a)-411.2(4-h)-412.2(treatment,)-421.6(human)-416.8(heart)-411.1(failure)]TJ -1.0137 -1.1116 TD [(therapeutic)-310.9(drugs,)-308.2(LCZ696,)-307.2(digoxin,)-305.2(irbesartan,)-311.7(metoprolol,)]TJ 0 -1.1174 TD [(qiliqiangxin)-418.2(capsule,)-423.5(enalapril,)-420.4(shenmai)-420.1(injection,)-425.1(and)-419.2(hy-)]TJ 0 -1.1116 TD [(drochlorothiazide,)-315.3(signi辌antly)-315.2(reduced)-316.4(heart)-313.2(dilatation)-319.3(and)]TJ T* [(venous)-203.4(congestion)-203.5(\(Fig.)-203.6(1\).)-207.2(The)-201.5(reduction%)-210.5(of)-198(enlarged)-208.2(heart)]TJ 0 -1.1174 TD [(wa)18.8(s)-179.5(2)0(0)20.8(%)0()19.8(9)0(0)15.1(%)-180.7(fo)20.9(r)-179.6(L)0(C)18.6(Z)0(6)19.6(9)0(6)20.8(,)]TJ /F8 1 Tf 11.0932 0 TD (-)Tj /F5 1 Tf .5414 0 TD [(1%)19.8(7)20.8(0%)-170.3(fo)15.1(r)-179.6(d)0(i)20.7(g)0(o)20.8(x)0(i)20.7(n)0(,)-171.6(2)0(0)20.8(%)0()19.8(6)0(7)15.1(%)]TJ -11.6346 -1.1116 TD [(fo)20.9(r)-335.1(i)0(r)20.7(b)0(e)19.7(s)0(a)19.9(r)0(t)15(a)0(n)19.7(,)-331.7(1%)19.8(6)20.8(3%)-325.8(fo)20.9(r)-335.1(m)0(e)18.4(t)0(o)20.7(p)0(r)20.9(o)0(l)20.7(o)0(l)15(,)-331.7(12)20.8(%)19.8(10)20.8(1%)-325.8(fo)20.9(r)-335.1(q)0(i)20.7(l)0(i)20.6(-)]TJ T* [(qi)20.7(an)19.7(gx)20.8(in)-572.5(ca)18.5(ps)21(ul)20.7(e,)-570.1(16)20.8(%)19.8(90)20.8(%)-583.9(f)0(o)20.9(r)-577(en)19.7(al)19.5(ap)19.7(ri)15(l,)-569.1(17)20.8(%)19.8(98)20.8(%)-578.1(f)0(o)20.9(r)]TJ 0 -1.1174 TD [(sh)21(en)19.7(ma)18.4(i)-502.3(i)0(n)20.7(j)0(e)19.6(c)0(t)19.6(i)0(o)20.7(n)0(,)-494.1(a)0(n)19.7(d)-496.4(12)15.1(%)19.8(75)20.8(%)-497.5(f)0(o)15.1(r)-496.4(hy)20.8(dr)15.1(oc)19.7(hl)20.7(or)20.9(ot)20.7(hi)14.9(az)18.5(id)20.7(e,)]TJ 0 -1.1116 TD [(re)19.7(sp)21(ec)18.5(ti)14.8(ve)19.7(ly)20.7(.)-567.9(S)0(t)20.9(a)0(t)19.5(i)0(s)20.9(t)0(i)20.6(c)0(a)12.8(l)0(l)20.6(y)-565.5(si)20.9(gn)20.8(i)15.1(ca)18.5(nt)-555.3(pr)20.9(ev)19.7(en)19.7(ti)14.8(ve)-556.3(ef)19.7(fe)19.7(ct)19.5(s)-565.4(o)0(n)]TJ T* [(ze)18.5(br)20.9(a)19.8(sh)-226.6(he)19.7(ar)19.7(t)-231.6(d)0(i)20.7(l)0(a)19.5(t)0(a)19.6(t)0(i)14.8(o)0(n)-221.1(w)0(e)18.8(r)0(e)-222.2(o)0(b)20.8(s)0(e)14.1(r)0(v)20.9(e)0(d)-222.2(f)0(o)20.9(r)-231.4(LC)18.6(Z6)19.6(96)15.1(,)-228.1(d)0(i)20.7(g)0(o)15.1(x)0(i)20.7(n)0(,)]TJ 0 -1.1174 TD [(ir)20.7(be)19.7(sa)19.9(rt)15(an)19.7(,)-372(m)0(e)18.4(t)0(o)15(p)0(r)20.9(o)0(l)20.7(o)0(l)20.7(,)-377.8(qi)20.7(li)20.6(qi)14.9(an)19.7(gx)20.8(in)-365.2(ca)18.5(ps)15.3(ul)20.7(e,)-362.8(en)13.9(al)19.6(ap)19.7(ri)20.7(l,)-367.5(sh)21(en)19.7(-)]TJ 0 -1.1116 TD [(ma)18.4(i)-266.2(i)0(n)15(j)0(e)19.6(c)0(t)19.5(i)0(o)20.7(n)0(,)-263.7(a)0(n)19.7(d)-266(hy)15.1(dr)20.9(oc)19.7(hl)20.7(or)20.9(ot)14.9(hi)20.7(az)18.5(id)20.7(e)-273(\()0(T)19.7(a)0(b)19.7(l)0(e)-262.7(1)-266(an)13.9(d)-266(F)0(i)20.9(g)0(.)-263.7(2)0(\))20.9(.)]TJ 1.0137 -1.1116 TD [(The)-385.8(reduction%)-389(of)-382.3(venous)-387.7(congestion)-387.8(was)-385.3(7%89%)-388.9(for)]TJ -1.0137 -1.1116 TD [(LCZ696,)-491.5(5%84%)-498.3(for)-492.8(digoxin,)-489.5(27%49%)-493.7(for)-498.6(irbesartan,)]TJ 0 -1.1174 TD [(2%43%)-308.3(for)-308.5(metoprolol,)-310.9(2%75%)-314(for)-308.5(qiliqiangxin)-308.8(capsule,)]TJ 0 -1.1116 TD [(7%94%)-256.4(for)-256.7(enalapril,)-259.1(16%83%)-257.5(for)-256.7(shenmai)-258.9(injection,)-258.1(and)]TJ /F8 1 Tf T* (-)Tj /F5 1 Tf .5529 0 TD [(3%)-343.1(to)-342.1(73%)-344.2(for)-343.1(hydrochlorothiazide,)-352(respectively.)-349.8(Statisti-)]TJ -.5529 -1.1174 TD [(cally)-290.3(signi辌ant)-289.8(preventive)-291.2(effects)-287.5(on)-290.2(zebra辳h)-288.4(venous)-289.8(con-)]TJ 0 -1.1116 TD [(gestion)-584.9(were)-583.5(observed)-586.9(for)-585(LCZ696,)-583.7(digoxin,)-587.4(irbesartan,)]TJ T* [(metoprolol,)-426.1(qiliqiangxin)-424(capsule,)-423.5(enalapril,)-426.1(shenmai)-425.9(injec-)]TJ 0 -1.1174 TD [(tion,)-278.8(and)-280.9(hydrochlorothiazide)-285.2(\(Table)-286.7(1)-277.6(and)-280.9(Fig.)-283.2(3\).)]TJ 1.0137 -1.1116 TD [(The)-449.2(increase)-462.6(in%)-448(of)-457.2(cardiac)-456(output)-456.1(was)-454.4(0%123%)-453.3(for)]TJ -1.0137 -1.1116 TD [(LCZ696,)-330.3(7%50%)-325.5(for)-331.5(digoxin,)]TJ /F8 1 Tf 13.1033 0 TD (-)Tj /F5 1 Tf .5529 0 TD [(2%)-325.8(to)-330.6(62%)-326.9(for)-325.8(irbesa)-8.8(rtan,)]TJ -13.6563 -1.1174 TD [(2%56%)-227.6(for)-222.1(metoprolol,)-230.3(10%90%)-223(for)-227.9(qiliqiangxin)-228.1(capsule,)]TJ /F8 1 Tf 0 -1.1116 TD (-)Tj /F5 1 Tf .5529 0 TD [(3%)-297(to)-301.8(51%)-303.9(for)-297(enalapril,)-305.2(27%81%)-303.6(for)-302.7(shenmai)-299.2(injection,)]TJ /F4 1 Tf 8.9663 0 0 8.9663 59.7543 749.7069 Tm [(HEART)-340.8(FAILURE)-337.3(MODEL)]TJ 54.1178 0 TD (3)Tj ET endstream endobj 57 0 obj <>stream 0 0 0 rg /GS1 gs 62.022 733.549 490.167 .22675 re f 62.022 72.907 490.167 .28348 re f 62.022 705.883 490.167 .28345 re f BT /F10 1 Tf 9.845 0 0 9.845 91.7858 749.1967 Tm 0 Tc 0 Tw (Table)Tj /F5 1 Tf 3.0002 0 TD (1.)Tj /F10 1 Tf 1.2496 0 TD [(Drug)-339.8(Ef辌acy)-332.2(on)-337(Heart)-333.8(Dilatation,)-331.8(Venous)-337(Congestion,)-332.8(Cardiac)-335.8(Output,)-336.1(and)-332(Blood)]TJ 5.0502 -1.0135 TD [(Flow)-333(Dynamics)-333(in)-337.3(the)-332.4(Zebra辳h)-333.2(Heart)-333.8(Failure)-336.2(Model)]TJ /F7 1 Tf 9.347 0 0 9.347 62.022 712.1195 Tm [(Drugs)-6773.8(Concentrations/dosage)-12.1(s)]TJ 19.7853 1.0129 TD [(Ef辌acy)-342.5(on)-328.3(heart)]TJ .6429 -1.0129 TD [(dilatation)-334.7(\(%\))]TJ 7.2239 1.0129 TD [(Ef辌acy)-336.5(on)-334.4(venous)]TJ .7582 -1.0129 TD [(congestion)-335.4(\(%\))]TJ 9.3892 1.0129 TD [(Ef辌acy)-336.5(on)]TJ -1.6134 -1.0129 TD [(cardiac)-336.6(output)-337.2(\(%\))]TJ 8.8494 1.0129 TD [(Ef辌)-7.9(acy)-334.6(on)-334.4(blood)]TJ -.2123 -1.0129 TD [(遫w)-335.6(dynamics)-340.4(\(%\))]TJ /F5 1 Tf -44.8232 -1.9045 TD [(LCZ696)-7754.1(0.005)]TJ /F6 1 Tf 13.5683 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 214.0724 698.4565 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 694.3179 Tm [(20)-7449.1(7)-8300.9(0)-7858.1(6)]TJ -11.7305 -1.0129 TD (0.01)Tj /F6 1 Tf 1.9227 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 688.9888 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 684.8502 Tm (31)Tj 7.0101 0 0 6.2305 285.222 688.9888 Tm (a)Tj 9.347 0 0 9.347 350.2487 684.8502 Tm [(17)-7825.1(13)-7309.6(14)]TJ -19.6882 -1.0129 TD (0.025)Tj /F6 1 Tf 2.4201 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 214.0724 679.5778 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.5275 675.3825 Tm (48)Tj 7.0101 0 0 6.2305 284.8818 679.5778 Tm (b)Tj 9.347 0 0 9.347 350.3621 675.3825 Tm (34)Tj 7.0101 0 0 6.2305 359.7164 679.5778 Tm (a)Tj 9.347 0 0 9.347 432.7369 675.3825 Tm [(23)-7309.6(16)]TJ -28.5134 -1.0129 TD (0.05)Tj /F6 1 Tf 1.9227 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 670.11 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 665.9148 Tm (64)Tj 7.0101 0 0 6.2305 285.222 670.11 Tm (c)Tj 9.347 0 0 9.347 350.3621 665.9148 Tm (51)Tj 7.0101 0 0 6.2305 359.7164 670.11 Tm (c)Tj 9.347 0 0 9.347 432.3967 665.9148 Tm (44)Tj 7.0101 0 0 6.2305 441.751 670.11 Tm (b)Tj 9.347 0 0 9.347 510.5196 665.9148 Tm (36)Tj 7.0101 0 0 6.2305 519.8739 670.11 Tm (a)Tj 9.347 0 0 9.347 166.2236 656.4471 Tm (0.1)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 660.6423 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 656.4471 Tm (71)Tj 7.0101 0 0 6.2305 285.222 660.6423 Tm (c)Tj 9.347 0 0 9.347 350.3621 656.4471 Tm (79)Tj 7.0101 0 0 6.2305 359.7164 660.6423 Tm (c)Tj 9.347 0 0 9.347 432.7936 656.4471 Tm (92)Tj 7.0101 0 0 6.2305 442.1479 660.6423 Tm (c)Tj 9.347 0 0 9.347 510.5196 656.4471 Tm (59)Tj 7.0101 0 0 6.2305 519.8739 660.6423 Tm (c)Tj 9.347 0 0 9.347 166.2236 646.9794 Tm (0.25)Tj /F6 1 Tf 1.9227 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 651.1746 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 646.9794 Tm (80)Tj 7.0101 0 0 6.2305 285.222 651.1746 Tm (c)Tj 9.347 0 0 9.347 350.3621 646.9794 Tm (81)Tj 7.0101 0 0 6.2305 359.7164 651.1746 Tm (c)Tj 9.347 0 0 9.347 428.0881 646.9794 Tm (123)Tj 7.0101 0 0 6.2305 442.1479 651.1746 Tm (c)Tj 9.347 0 0 9.347 510.5196 646.9794 Tm (66)Tj 7.0101 0 0 6.2305 519.8739 651.1746 Tm (c)Tj 9.347 0 0 9.347 166.2236 637.5117 Tm (0.5)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 641.7069 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 637.5117 Tm (90)Tj 7.0101 0 0 6.2305 285.222 641.7069 Tm (c)Tj 9.347 0 0 9.347 350.3621 637.5117 Tm (89)Tj 7.0101 0 0 6.2305 359.7164 641.7069 Tm (c)Tj 9.347 0 0 9.347 432.3967 637.5117 Tm (65)Tj 7.0101 0 0 6.2305 441.751 641.7069 Tm (b)Tj 9.347 0 0 9.347 510.1794 637.5117 Tm (26)Tj 7.0101 0 0 6.2305 519.5338 641.7069 Tm (b)Tj 9.347 0 0 9.347 166.2236 628.1006 Tm (1)Tj /F6 1 Tf .6672 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 197.6881 632.2392 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 628.1006 Tm (51)Tj 7.0101 0 0 6.2305 285.222 632.2392 Tm (c)Tj 9.347 0 0 9.347 350.0219 628.1006 Tm (36)Tj 7.0101 0 0 6.2305 359.3763 632.2392 Tm (b)Tj 9.347 0 0 9.347 432.7369 628.1006 Tm [(18)-7309.6(14)]TJ -28.5134 -1.0129 TD (2.5)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 622.7715 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 618.6329 Tm (39)Tj 7.0101 0 0 6.2305 285.222 622.7715 Tm (a)Tj 9.347 0 0 9.347 350.2487 618.6329 Tm (22)Tj /F8 1 Tf 8.8009 0 TD (-)Tj /F5 1 Tf .5519 0 TD 7.7732 Tc (79)Tj -40.1892 -1.0129 TD 0 Tc [(Digoxin)-7868.1(0.01)]TJ /F6 1 Tf 13.0709 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 613.3038 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj /F8 1 Tf 9.347 0 0 9.347 275.3574 609.1652 Tm (-)Tj /F5 1 Tf .552 0 TD 7.4517 Tc [(15)-903.8(7)84.9(1)7451.7(1)]TJ -12.2278 -1.0129 TD 0 Tc (0.025)Tj /F6 1 Tf 2.4201 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 214.0724 603.8361 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 599.6975 Tm [(11)-6957.8(22)-7825.1(11)-7321.7(17)]TJ 7.0101 0 0 6.2305 519.8739 603.8361 Tm (a)Tj 9.347 0 0 9.347 166.2236 590.2297 Tm (0.05)Tj /F6 1 Tf 1.9227 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 594.3683 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.6409 590.2297 Tm [(16)-6982(27)-7831.2(27)]TJ 7.0101 0 0 6.2305 442.1479 594.3683 Tm (a)Tj 9.347 0 0 9.347 510.1794 590.2297 Tm (20)Tj 7.0101 0 0 6.2305 519.5338 594.3683 Tm (b)Tj 9.347 0 0 9.347 166.2236 580.7621 Tm (0.1)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 584.9006 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 580.7621 Tm (35)Tj 7.0101 0 0 6.2305 285.222 584.9006 Tm (a)Tj 9.347 0 0 9.347 350.3621 580.7621 Tm (35)Tj 7.0101 0 0 6.2305 359.7164 584.9006 Tm (a)Tj 9.347 0 0 9.347 432.3967 580.7621 Tm (34)Tj 7.0101 0 0 6.2305 441.751 584.9006 Tm (b)Tj 9.347 0 0 9.347 510.1794 580.7621 Tm (28)Tj 7.0101 0 0 6.2305 519.5338 584.9006 Tm (b)Tj 9.347 0 0 9.347 166.2236 571.2943 Tm (0.25)Tj /F6 1 Tf 1.9227 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 575.4329 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.5275 571.2943 Tm (47)Tj 7.0101 0 0 6.2305 284.8818 575.4329 Tm (b)Tj 9.347 0 0 9.347 350.0219 571.2943 Tm (45)Tj 7.0101 0 0 6.2305 359.3763 575.4329 Tm (b)Tj 9.347 0 0 9.347 432.7936 571.2943 Tm (50)Tj 7.0101 0 0 6.2305 442.1479 575.4329 Tm (c)Tj 9.347 0 0 9.347 510.5196 571.2943 Tm (30)Tj 7.0101 0 0 6.2305 519.8739 575.4329 Tm (c)Tj 9.347 0 0 9.347 166.2236 561.8266 Tm (0.5)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 565.9652 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.5275 561.8266 Tm (53)Tj 7.0101 0 0 6.2305 284.8818 565.9652 Tm (b)Tj 9.347 0 0 9.347 350.3621 561.8266 Tm (73)Tj 7.0101 0 0 6.2305 359.7164 565.9652 Tm (c)Tj 9.347 0 0 9.347 432.3967 561.8266 Tm (40)Tj 7.0101 0 0 6.2305 441.751 565.9652 Tm (b)Tj 9.347 0 0 9.347 510.1794 561.8266 Tm (28)Tj 7.0101 0 0 6.2305 519.5338 565.9652 Tm (b)Tj 9.347 0 0 9.347 166.2236 552.3589 Tm (1)Tj /F6 1 Tf .6672 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 197.6881 556.4975 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.5275 552.3589 Tm (56)Tj 7.0101 0 0 6.2305 284.8818 556.4975 Tm (b)Tj 9.347 0 0 9.347 350.3621 552.3589 Tm (84)Tj 7.0101 0 0 6.2305 359.7164 556.4975 Tm (c)Tj 9.347 0 0 9.347 432.7936 552.3589 Tm (36)Tj 7.0101 0 0 6.2305 442.1479 556.4975 Tm (c)Tj 9.347 0 0 9.347 510.5196 552.3589 Tm (18)Tj 7.0101 0 0 6.2305 519.8739 556.4975 Tm (a)Tj 9.347 0 0 9.347 166.2236 542.8912 Tm (2.5)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 547.0298 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 542.8912 Tm (59)Tj 7.0101 0 0 6.2305 285.222 547.0298 Tm (c)Tj 9.347 0 0 9.347 350.3621 542.8912 Tm (73)Tj 7.0101 0 0 6.2305 359.7164 547.0298 Tm (c)Tj 9.347 0 0 9.347 432.7936 542.8912 Tm (25)Tj 7.0101 0 0 6.2305 442.1479 547.0298 Tm (a)Tj 9.347 0 0 9.347 510.5196 542.8912 Tm (14)Tj 7.0101 0 0 6.2305 519.8739 547.0298 Tm (a)Tj 9.347 0 0 9.347 166.2236 533.4235 Tm (5)Tj /F6 1 Tf .6672 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 197.6881 537.5621 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 533.4235 Tm (60)Tj 7.0101 0 0 6.2305 285.222 537.5621 Tm (c)Tj 9.347 0 0 9.347 350.0219 533.4235 Tm (35)Tj 7.0101 0 0 6.2305 359.3763 537.5621 Tm (b)Tj 9.347 0 0 9.347 432.7369 533.4235 Tm [(20)-7800.9(9)]TJ -28.5134 -1.0129 TD (10)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 528.0944 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 523.9557 Tm (70)Tj 7.0101 0 0 6.2305 285.222 528.0944 Tm (c)Tj 9.347 0 0 9.347 350.2487 523.9557 Tm (27)Tj /F8 1 Tf 8.7766 0 TD (-)Tj /F5 1 Tf .5519 0 TD 7.7975 Tc (25)Tj -40.165 -1.0129 TD 0 Tc [(Irbesartan)-7142.1(0.1)]TJ /F6 1 Tf 12.5675 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 518.6266 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.6409 514.488 Tm [(20)-6994.2(27)]TJ 7.0101 0 0 6.2305 359.7164 518.6266 Tm (a)Tj /F8 1 Tf 9.347 0 0 9.347 432.2833 514.488 Tm (-)Tj /F5 1 Tf .5519 0 TD (2)Tj /F8 1 Tf 7.7819 0 TD (-)Tj /F5 1 Tf .552 0 TD (1)Tj -37.3506 -1.0129 TD (0.25)Tj /F6 1 Tf 1.9227 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 509.1589 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.6409 505.0203 Tm [(24)-6994.2(34)]TJ 7.0101 0 0 6.2305 359.7164 509.1589 Tm (a)Tj 9.347 0 0 9.347 432.7936 505.0203 Tm (22)Tj 7.0101 0 0 6.2305 442.1479 509.1589 Tm (a)Tj 9.347 0 0 9.347 514.9983 505.0203 Tm (9)Tj -37.3143 -1.0129 TD (0.5)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 499.7479 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 495.5526 Tm (30)Tj 7.0101 0 0 6.2305 285.222 499.7479 Tm (a)Tj 9.347 0 0 9.347 350.0219 495.5526 Tm (36)Tj 7.0101 0 0 6.2305 359.3763 499.7479 Tm (b)Tj 9.347 0 0 9.347 432.7936 495.5526 Tm (25)Tj 7.0101 0 0 6.2305 442.1479 499.7479 Tm (a)Tj 9.347 0 0 9.347 510.4062 495.5526 Tm (15)Tj -36.823 -1.0129 TD (1)Tj /F6 1 Tf .6672 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 197.6881 490.2802 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 486.0849 Tm (36)Tj 7.0101 0 0 6.2305 285.222 490.2802 Tm (a)Tj 9.347 0 0 9.347 350.0219 486.0849 Tm (40)Tj 7.0101 0 0 6.2305 359.3763 490.2802 Tm (b)Tj 9.347 0 0 9.347 432.7936 486.0849 Tm (28)Tj 7.0101 0 0 6.2305 442.1479 490.2802 Tm (a)Tj 9.347 0 0 9.347 510.5196 486.0849 Tm (16)Tj 7.0101 0 0 6.2305 519.8739 490.2802 Tm (a)Tj 9.347 0 0 9.347 166.2236 476.6172 Tm (2.5)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 480.8125 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.5275 476.6172 Tm (38)Tj 7.0101 0 0 6.2305 284.8818 480.8125 Tm (b)Tj 9.347 0 0 9.347 350.3621 476.6172 Tm (41)Tj 7.0101 0 0 6.2305 359.7164 480.8125 Tm (c)Tj 9.347 0 0 9.347 432.7936 476.6172 Tm (33)Tj 7.0101 0 0 6.2305 442.1479 480.8125 Tm (a)Tj 9.347 0 0 9.347 510.5196 476.6172 Tm (23)Tj 7.0101 0 0 6.2305 519.8739 480.8125 Tm (a)Tj 9.347 0 0 9.347 166.2236 467.1495 Tm (5)Tj /F6 1 Tf .6672 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 197.6881 471.3448 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 467.1495 Tm (43)Tj 7.0101 0 0 6.2305 285.222 471.3448 Tm (c)Tj 9.347 0 0 9.347 350.0219 467.1495 Tm (43)Tj 7.0101 0 0 6.2305 359.3763 471.3448 Tm (b)Tj 9.347 0 0 9.347 432.7936 467.1495 Tm (55)Tj 7.0101 0 0 6.2305 442.1479 471.3448 Tm (c)Tj 9.347 0 0 9.347 510.1794 467.1495 Tm (30)Tj 7.0101 0 0 6.2305 519.5338 471.3448 Tm (b)Tj 9.347 0 0 9.347 166.2236 457.7385 Tm (10)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 461.877 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 457.7385 Tm (67)Tj 7.0101 0 0 6.2305 285.222 461.877 Tm (c)Tj 9.347 0 0 9.347 350.3621 457.7385 Tm (49)Tj 7.0101 0 0 6.2305 359.7164 461.877 Tm (c)Tj 9.347 0 0 9.347 432.7936 457.7385 Tm (62)Tj 7.0101 0 0 6.2305 442.1479 461.877 Tm (c)Tj 9.347 0 0 9.347 510.1794 457.7385 Tm (31)Tj 7.0101 0 0 6.2305 519.5338 461.877 Tm (b)Tj 9.347 0 0 9.347 62.022 448.2708 Tm [(Metoprolol)-6640.1(0.025)]TJ /F6 1 Tf 13.5683 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 214.0724 452.4093 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 280.1763 448.2708 Tm 7.4881 Tc [(12)-812.8(4)-345.7(0)]TJ -12.1914 -1.0129 TD 0 Tc (0.05)Tj /F6 1 Tf 1.9227 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 442.9416 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 438.803 Tm (19)Tj 7.0101 0 0 6.2305 285.222 442.9416 Tm (a)Tj 9.347 0 0 9.347 354.8409 438.803 Tm 8.3009 Tc [(72)412.5(1)]TJ -20.1795 -1.0129 TD 0 Tc (0.1)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 433.4739 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 429.3353 Tm (25)Tj 7.0101 0 0 6.2305 285.222 433.4739 Tm (a)Tj 9.347 0 0 9.347 350.7589 429.3353 Tm [(11)-7770.5(11)-7800.9(6)]TJ -19.7428 -1.0129 TD (0.25)Tj /F6 1 Tf 1.9227 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 424.0062 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.5275 419.8676 Tm (31)Tj 7.0101 0 0 6.2305 284.8818 424.0062 Tm (b)Tj 9.347 0 0 9.347 350.2487 419.8676 Tm [(26)-7831.2(30)]TJ 7.0101 0 0 6.2305 442.1479 424.0062 Tm (c)Tj 9.347 0 0 9.347 510.5196 419.8676 Tm (13)Tj 7.0101 0 0 6.2305 519.8739 424.0062 Tm (a)Tj 9.347 0 0 9.347 166.2236 410.3999 Tm (0.5)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 414.5385 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.5275 410.3999 Tm (34)Tj 7.0101 0 0 6.2305 284.8818 414.5385 Tm (b)Tj 9.347 0 0 9.347 350.3621 410.3999 Tm (29)Tj 7.0101 0 0 6.2305 359.7164 414.5385 Tm (a)Tj 9.347 0 0 9.347 432.7936 410.3999 Tm (35)Tj 7.0101 0 0 6.2305 442.1479 414.5385 Tm (c)Tj 9.347 0 0 9.347 510.5196 410.3999 Tm (17)Tj 7.0101 0 0 6.2305 519.8739 414.5385 Tm (a)Tj 9.347 0 0 9.347 166.2236 400.9322 Tm (1)Tj /F6 1 Tf .6672 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 197.6881 405.0708 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 400.9322 Tm (63)Tj 7.0101 0 0 6.2305 285.222 405.0708 Tm (c)Tj 9.347 0 0 9.347 350.3621 400.9322 Tm (35)Tj 7.0101 0 0 6.2305 359.7164 405.0708 Tm (a)Tj 9.347 0 0 9.347 432.7936 400.9322 Tm (38)Tj 7.0101 0 0 6.2305 442.1479 405.0708 Tm (c)Tj 9.347 0 0 9.347 510.5196 400.9322 Tm (17)Tj 7.0101 0 0 6.2305 519.8739 405.0708 Tm (a)Tj 9.347 0 0 9.347 166.2236 391.4644 Tm (2.5)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 395.603 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 391.4644 Tm (40)Tj 7.0101 0 0 6.2305 285.222 395.603 Tm (c)Tj 9.347 0 0 9.347 350.0219 391.4644 Tm (41)Tj 7.0101 0 0 6.2305 359.3763 395.603 Tm (b)Tj 9.347 0 0 9.347 432.7936 391.4644 Tm (40)Tj 7.0101 0 0 6.2305 442.1479 395.603 Tm (c)Tj 9.347 0 0 9.347 510.5196 391.4644 Tm (20)Tj 7.0101 0 0 6.2305 519.8739 395.603 Tm (a)Tj 9.347 0 0 9.347 166.2236 381.9968 Tm (5)Tj /F6 1 Tf .6672 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 197.6881 386.1353 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.5275 381.9968 Tm (27)Tj 7.0101 0 0 6.2305 284.8818 386.1353 Tm (b)Tj 9.347 0 0 9.347 350.0219 381.9968 Tm (43)Tj 7.0101 0 0 6.2305 359.3763 386.1353 Tm (b)Tj 9.347 0 0 9.347 432.7936 381.9968 Tm (56)Tj 7.0101 0 0 6.2305 442.1479 386.1353 Tm (c)Tj 9.347 0 0 9.347 510.5196 381.9968 Tm (29)Tj 7.0101 0 0 6.2305 519.8739 386.1353 Tm (c)Tj 9.347 0 0 9.347 166.2236 372.529 Tm (10)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 376.6676 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 280.6865 372.529 Tm 7.8251 Tc [(6)882.9(1)7825.1(51)7825.1(31)]TJ -23.3942 -1.0129 TD 0 Tc [(Qiliqiangxin)-340.3(capsule)-2730.8(2.5)]TJ /F6 1 Tf 12.5675 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 367.1999 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.6409 363.0613 Tm [(12)-7473.3(2)-7833.8(1)0(0)-7825.1(1)]TJ -11.7062 -1.0129 TD (5)Tj /F6 1 Tf .6672 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 197.6881 357.7322 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 353.5936 Tm (47)Tj 7.0101 0 0 6.2305 285.222 357.7322 Tm (a)Tj 9.347 0 0 9.347 350.3621 353.5936 Tm (25)Tj 7.0101 0 0 6.2305 359.7164 357.7322 Tm (a)Tj 9.347 0 0 9.347 432.3967 353.5936 Tm (39)Tj 7.0101 0 0 6.2305 441.751 357.7322 Tm (b)Tj 9.347 0 0 9.347 510.4062 353.5936 Tm (12)Tj -36.823 -1.0129 TD (10)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 348.2645 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 344.1259 Tm (72)Tj 7.0101 0 0 6.2305 285.222 348.2645 Tm (c)Tj 9.347 0 0 9.347 350.3621 344.1259 Tm (46)Tj 7.0101 0 0 6.2305 359.7164 348.2645 Tm (c)Tj 9.347 0 0 9.347 432.7936 344.1259 Tm (65)Tj 7.0101 0 0 6.2305 442.1479 348.2645 Tm (c)Tj 9.347 0 0 9.347 510.1794 344.1259 Tm (41)Tj 7.0101 0 0 6.2305 519.5338 348.2645 Tm (b)Tj 9.347 0 0 9.347 166.2236 334.6582 Tm (25)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 338.7968 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 271.2188 334.6582 Tm (101)Tj 7.0101 0 0 6.2305 285.222 338.7968 Tm (c)Tj 9.347 0 0 9.347 350.3621 334.6582 Tm (75)Tj 7.0101 0 0 6.2305 359.7164 338.7968 Tm (c)Tj 9.347 0 0 9.347 432.7936 334.6582 Tm (90)Tj 7.0101 0 0 6.2305 442.1479 338.7968 Tm (c)Tj 9.347 0 0 9.347 510.5196 334.6582 Tm (66)Tj 7.0101 0 0 6.2305 519.8739 338.7968 Tm (c)Tj 9.347 0 0 9.347 166.2236 325.1905 Tm (50)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 329.3857 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 325.1905 Tm (87)Tj 7.0101 0 0 6.2305 285.222 329.3857 Tm (c)Tj 9.347 0 0 9.347 350.3621 325.1905 Tm (52)Tj 7.0101 0 0 6.2305 359.7164 329.3857 Tm (c)Tj 9.347 0 0 9.347 432.7936 325.1905 Tm (62)Tj 7.0101 0 0 6.2305 442.1479 329.3857 Tm (c)Tj 9.347 0 0 9.347 510.5196 325.1905 Tm (34)Tj 7.0101 0 0 6.2305 519.8739 329.3857 Tm (a)Tj 9.347 0 0 9.347 166.2236 315.7227 Tm (100)Tj /F6 1 Tf 1.668 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 207.0425 319.918 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 315.7227 Tm (76)Tj 7.0101 0 0 6.2305 285.222 319.918 Tm (c)Tj 9.347 0 0 9.347 350.3621 315.7227 Tm (45)Tj 7.0101 0 0 6.2305 359.7164 319.918 Tm (c)Tj 9.347 0 0 9.347 432.7936 315.7227 Tm (44)Tj 7.0101 0 0 6.2305 442.1479 319.918 Tm (a)Tj 9.347 0 0 9.347 510.5196 315.7227 Tm (27)Tj 7.0101 0 0 6.2305 519.8739 319.918 Tm (a)Tj 9.347 0 0 9.347 166.2236 306.255 Tm (250)Tj /F6 1 Tf 1.668 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 207.0425 310.4503 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 306.255 Tm (44)Tj 7.0101 0 0 6.2305 285.222 310.4503 Tm (a)Tj 9.347 0 0 9.347 354.8409 306.255 Tm 7.8338 Tc [(21)7833.8(7)32.9(2)]TJ -31.3277 -1.0129 TD 0 Tc [(Enalapril)-7464.1(5)]TJ /F6 1 Tf 11.8154 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 197.6881 300.9826 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 296.7873 Tm [(16)-7449.1(7)]TJ /F8 1 Tf 16.7587 0 TD (-)Tj /F5 1 Tf .5519 0 TD 7.7732 Tc (31)Tj -29.0411 -1.0129 TD 0 Tc (10)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 291.5149 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 287.3196 Tm (31)Tj 7.0101 0 0 6.2305 285.222 291.5149 Tm (a)Tj 9.347 0 0 9.347 350.3621 287.3196 Tm (34)Tj 7.0101 0 0 6.2305 359.7164 291.5149 Tm (a)Tj 9.347 0 0 9.347 432.3967 287.3196 Tm (34)Tj 7.0101 0 0 6.2305 441.751 291.5149 Tm (b)Tj 9.347 0 0 9.347 510.1794 287.3196 Tm (26)Tj 7.0101 0 0 6.2305 519.5338 291.5149 Tm (b)Tj 9.347 0 0 9.347 166.2236 277.9086 Tm (25)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 282.0472 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.5275 277.9086 Tm (50)Tj 7.0101 0 0 6.2305 284.8818 282.0472 Tm (b)Tj 9.347 0 0 9.347 350.3621 277.9086 Tm (56)Tj 7.0101 0 0 6.2305 359.7164 282.0472 Tm (c)Tj 9.347 0 0 9.347 432.7936 277.9086 Tm (51)Tj 7.0101 0 0 6.2305 442.1479 282.0472 Tm (c)Tj 9.347 0 0 9.347 510.1794 277.9086 Tm (33)Tj 7.0101 0 0 6.2305 519.5338 282.0472 Tm (b)Tj 9.347 0 0 9.347 166.2236 268.4409 Tm (50)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 272.5794 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.5275 268.4409 Tm (54)Tj 7.0101 0 0 6.2305 284.8818 272.5794 Tm (b)Tj 9.347 0 0 9.347 350.3621 268.4409 Tm (60)Tj 7.0101 0 0 6.2305 359.7164 272.5794 Tm (c)Tj 9.347 0 0 9.347 432.7936 268.4409 Tm (51)Tj 7.0101 0 0 6.2305 442.1479 272.5794 Tm (c)Tj 9.347 0 0 9.347 510.5196 268.4409 Tm (42)Tj 7.0101 0 0 6.2305 519.8739 272.5794 Tm (c)Tj 9.347 0 0 9.347 166.2236 258.9731 Tm (100)Tj /F6 1 Tf 1.668 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 207.0425 263.1117 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 258.9731 Tm (66)Tj 7.0101 0 0 6.2305 285.222 263.1117 Tm (c)Tj 9.347 0 0 9.347 350.3621 258.9731 Tm (87)Tj 7.0101 0 0 6.2305 359.7164 263.1117 Tm (c)Tj 9.347 0 0 9.347 432.3967 258.9731 Tm (33)Tj 7.0101 0 0 6.2305 441.751 263.1117 Tm (b)Tj 9.347 0 0 9.347 510.5196 258.9731 Tm (20)Tj 7.0101 0 0 6.2305 519.8739 263.1117 Tm (a)Tj 9.347 0 0 9.347 166.2236 249.5054 Tm (250)Tj /F6 1 Tf 1.668 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 207.0425 253.644 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 249.5054 Tm (90)Tj 7.0101 0 0 6.2305 285.222 253.644 Tm (c)Tj 9.347 0 0 9.347 350.3621 249.5054 Tm (94)Tj 7.0101 0 0 6.2305 359.7164 253.644 Tm (c)Tj 9.347 0 0 9.347 432.7369 249.5054 Tm [(19)-7339.9(19)]TJ -39.6616 -1.0129 TD [(Shenmai)-337.4(injection)-3784.7(0.3125)-167.4(ng)-7813(17)-6957.8(16)-7831.2(27)]TJ 7.0101 0 0 6.2305 442.1479 244.1763 Tm (a)Tj 9.347 0 0 9.347 510.5196 240.0378 Tm (19)Tj 7.0101 0 0 6.2305 519.8739 244.1763 Tm (a)Tj 9.347 0 0 9.347 166.2236 230.57 Tm [(0.625)-170.1(ng)-8310.4(38)]TJ 7.0101 0 0 6.2305 285.222 234.7086 Tm (a)Tj 9.347 0 0 9.347 350.3621 230.57 Tm (39)Tj 7.0101 0 0 6.2305 359.7164 234.7086 Tm (c)Tj 9.347 0 0 9.347 432.7936 230.57 Tm (48)Tj 7.0101 0 0 6.2305 442.1479 234.7086 Tm (c)Tj 9.347 0 0 9.347 510.5196 230.57 Tm (23)Tj 7.0101 0 0 6.2305 519.8739 234.7086 Tm (a)Tj 9.347 0 0 9.347 166.2236 221.1023 Tm [(1.25)-172.7(ng)-8807.7(75)]TJ 7.0101 0 0 6.2305 285.222 225.2409 Tm (c)Tj 9.347 0 0 9.347 350.3621 221.1023 Tm (62)Tj 7.0101 0 0 6.2305 359.7164 225.2409 Tm (c)Tj 9.347 0 0 9.347 432.7936 221.1023 Tm (52)Tj 7.0101 0 0 6.2305 442.1479 225.2409 Tm (c)Tj 9.347 0 0 9.347 510.5196 221.1023 Tm (26)Tj 7.0101 0 0 6.2305 519.8739 225.2409 Tm (a)Tj 9.347 0 0 9.347 166.2236 211.6346 Tm [(2.5)-169.3(ng)-9274.8(98)]TJ 7.0101 0 0 6.2305 284.8818 215.7732 Tm (b)Tj 9.347 0 0 9.347 350.3621 211.6346 Tm (83)Tj 7.0101 0 0 6.2305 359.7164 215.7732 Tm (c)Tj 9.347 0 0 9.347 432.7936 211.6346 Tm (72)Tj 7.0101 0 0 6.2305 442.1479 215.7732 Tm (c)Tj 9.347 0 0 9.347 510.1794 211.6346 Tm (31)Tj 7.0101 0 0 6.2305 519.5338 215.7732 Tm (b)Tj 9.347 0 0 9.347 166.2236 202.1668 Tm .1672 Tc [(5n)167.2(g)-9859.7(6)167.2(0)]TJ 7.0101 0 0 6.2305 284.8818 206.3054 Tm 0 Tc (b)Tj 9.347 0 0 9.347 350.3621 202.1668 Tm (63)Tj 7.0101 0 0 6.2305 359.7164 206.3054 Tm (c)Tj 9.347 0 0 9.347 432.7936 202.1668 Tm (81)Tj 7.0101 0 0 6.2305 442.1479 206.3054 Tm (c)Tj 9.347 0 0 9.347 510.1794 202.1668 Tm (35)Tj 7.0101 0 0 6.2305 519.5338 206.3054 Tm (b)Tj 9.347 0 0 9.347 166.2236 192.6991 Tm [(10)-170.6(ng)-10075.4(1)-6954.4(4)0(9)]TJ 7.0101 0 0 6.2305 359.7164 196.8377 Tm (c)Tj 9.347 0 0 9.347 432.7936 192.6991 Tm (25)Tj 7.0101 0 0 6.2305 442.1479 196.8377 Tm (a)Tj 9.347 0 0 9.347 515.3384 192.6991 Tm (9)Tj -48.4988 -1.0129 TD [(Hydrochlorothiazide)-2852.1(0.01)]TJ /F6 1 Tf 13.0709 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 187.37 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.6409 183.2314 Tm (12)Tj /F8 1 Tf 7.9578 0 TD (-)Tj /F5 1 Tf .552 0 TD 7.7186 Tc [(3)166.4()]TJ -20.2159 -1.0129 TD 0 Tc (0.025)Tj /F6 1 Tf 2.4201 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 214.0724 177.9023 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.6409 173.7638 Tm [(14)-6982(14)-7746.3()-7552.2()]TJ -11.7062 -1.0129 TD (0.05)Tj /F6 1 Tf 1.9227 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 168.4346 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 164.296 Tm (39)Tj 7.0101 0 0 6.2305 285.222 168.4346 Tm (a)Tj 9.347 0 0 9.347 350.0219 164.296 Tm (32)Tj 7.0101 0 0 6.2305 359.3763 168.4346 Tm (b)Tj 9.347 0 0 9.347 431.9999 164.296 Tm 7.5522 Tc (蜒)Tj -28.4345 -1.0129 TD 0 Tc (0.1)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 159.0236 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 154.8283 Tm (46)Tj 7.0101 0 0 6.2305 285.222 159.0236 Tm (a)Tj 9.347 0 0 9.347 350.0219 154.8283 Tm (43)Tj 7.0101 0 0 6.2305 359.3763 159.0236 Tm (b)Tj 9.347 0 0 9.347 432.7369 154.8283 Tm [(18)-7837.3(5)]TJ -28.5134 -1.0129 TD (0.25)Tj /F6 1 Tf 1.9227 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 209.3669 149.5559 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.8676 145.3606 Tm (49)Tj 7.0101 0 0 6.2305 285.222 149.5559 Tm (a)Tj 9.347 0 0 9.347 350.3621 145.3606 Tm (55)Tj 7.0101 0 0 6.2305 359.7164 149.5559 Tm (c)Tj 9.347 0 0 9.347 432.3967 145.3606 Tm (35)Tj 7.0101 0 0 6.2305 441.751 149.5559 Tm (b)Tj 9.347 0 0 9.347 510.6896 145.3606 Tm (23)Tj -36.8533 -1.0129 TD (0.5)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 140.0882 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.5275 135.8929 Tm (56)Tj 7.0101 0 0 6.2305 284.8818 140.0882 Tm (b)Tj 9.347 0 0 9.347 350.3621 135.8929 Tm (60)Tj 7.0101 0 0 6.2305 359.7164 140.0882 Tm (c)Tj 9.347 0 0 9.347 432.3967 135.8929 Tm (53)Tj 7.0101 0 0 6.2305 441.751 140.0882 Tm (b)Tj 9.347 0 0 9.347 510.5196 135.8929 Tm (33)Tj 7.0101 0 0 6.2305 519.8739 140.0882 Tm (a)Tj 9.347 0 0 9.347 166.2236 126.4252 Tm (1)Tj /F6 1 Tf .6672 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 197.6881 130.6204 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.5275 126.4252 Tm (62)Tj 7.0101 0 0 6.2305 284.8818 130.6204 Tm (b)Tj 9.347 0 0 9.347 350.3621 126.4252 Tm (62)Tj 7.0101 0 0 6.2305 359.7164 130.6204 Tm (c)Tj 9.347 0 0 9.347 432.3967 126.4252 Tm (67)Tj 7.0101 0 0 6.2305 441.751 130.6204 Tm (b)Tj 9.347 0 0 9.347 510.1794 126.4252 Tm (43)Tj 7.0101 0 0 6.2305 519.5338 130.6204 Tm (b)Tj 9.347 0 0 9.347 166.2236 116.9575 Tm (2.5)Tj /F6 1 Tf 1.4193 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 204.718 121.1527 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.5275 116.9575 Tm (68)Tj 7.0101 0 0 6.2305 284.8818 121.1527 Tm (b)Tj 9.347 0 0 9.347 350.3621 116.9575 Tm (63)Tj 7.0101 0 0 6.2305 359.7164 121.1527 Tm (c)Tj 9.347 0 0 9.347 432.7936 116.9575 Tm (69)Tj 7.0101 0 0 6.2305 442.1479 121.1527 Tm (c)Tj 9.347 0 0 9.347 510.5196 116.9575 Tm (49)Tj 7.0101 0 0 6.2305 519.8739 121.1527 Tm (c)Tj 9.347 0 0 9.347 166.2236 107.5464 Tm (5)Tj /F6 1 Tf .6672 0 TD (l)Tj /F5 1 Tf .552 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 197.6881 111.685 Tm (-)Tj /F5 1 Tf .558 0 TD (1)Tj 9.347 0 0 9.347 275.5275 107.5464 Tm (70)Tj 7.0101 0 0 6.2305 284.8818 111.685 Tm (b)Tj 9.347 0 0 9.347 350.3621 107.5464 Tm (67)Tj 7.0101 0 0 6.2305 359.7164 111.685 Tm (c)Tj 9.347 0 0 9.347 432.7936 107.5464 Tm (84)Tj 7.0101 0 0 6.2305 442.1479 111.685 Tm (c)Tj 9.347 0 0 9.347 510.5196 107.5464 Tm (53)Tj 7.0101 0 0 6.2305 519.8739 111.685 Tm (c)Tj 9.347 0 0 9.347 166.2236 98.0787 Tm (10)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 102.2173 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 98.0787 Tm (75)Tj 7.0101 0 0 6.2305 285.222 102.2173 Tm (c)Tj 9.347 0 0 9.347 350.3621 98.0787 Tm (73)Tj 7.0101 0 0 6.2305 359.7164 102.2173 Tm (c)Tj 9.347 0 0 9.347 432.7936 98.0787 Tm (68)Tj 7.0101 0 0 6.2305 442.1479 102.2173 Tm (c)Tj 9.347 0 0 9.347 510.5196 98.0787 Tm (52)Tj 7.0101 0 0 6.2305 519.8739 102.2173 Tm (c)Tj 9.347 0 0 9.347 166.2236 88.611 Tm (25)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 92.7496 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 88.611 Tm (43)Tj 7.0101 0 0 6.2305 285.222 92.7496 Tm (a)Tj 9.347 0 0 9.347 350.3621 88.611 Tm (47)Tj 7.0101 0 0 6.2305 359.7164 92.7496 Tm (c)Tj 9.347 0 0 9.347 432.7936 88.611 Tm (56)Tj 7.0101 0 0 6.2305 442.1479 92.7496 Tm (c)Tj 9.347 0 0 9.347 510.1794 88.611 Tm (44)Tj 7.0101 0 0 6.2305 519.5338 92.7496 Tm (b)Tj 9.347 0 0 9.347 166.2236 79.1433 Tm (50)Tj /F6 1 Tf 1.1706 0 TD (l)Tj /F5 1 Tf .5519 0 TD (g.mL)Tj /F8 1 Tf 7.0101 0 0 6.2305 202.3936 83.2819 Tm (-)Tj /F5 1 Tf .5499 0 TD (1)Tj 9.347 0 0 9.347 275.8676 79.1433 Tm [(33)-6933.5(40)]TJ 7.0101 0 0 6.2305 359.3763 83.2819 Tm (b)Tj 9.347 0 0 9.347 432.3967 79.1433 Tm (38)Tj 7.0101 0 0 6.2305 441.751 83.2819 Tm (b)Tj 9.347 0 0 9.347 510.1794 79.1433 Tm (37)Tj 7.0101 0 0 6.2305 519.5338 83.2819 Tm (b)Tj 8.7511 0 0 8.7511 70.0157 61.1149 Tm [(Compared)-328.5(with)-338.4(vehicle)-329.7(control:)]TJ 6.5633 0 0 5.8334 186.5196 65.0268 Tm (a)Tj /F7 1 Tf 8.7511 0 0 8.7511 189.4677 61.1149 Tm (p)Tj /F8 1 Tf .6673 0 TD (<)Tj /F5 1 Tf .7126 0 TD (0.05,)Tj 6.5633 0 0 5.8334 221.9527 65.0268 Tm (b)Tj /F7 1 Tf 8.7511 0 0 8.7511 225.2409 61.1149 Tm (p)Tj /F8 1 Tf .6673 0 TD (<)Tj /F5 1 Tf .7191 0 TD [(0.01,)-332.2(and)]TJ 6.5633 0 0 5.8334 273.3732 65.0268 Tm (c)Tj /F7 1 Tf 8.7511 0 0 8.7511 276.3212 61.1149 Tm (p)Tj /F8 1 Tf .6673 0 TD (<)Tj /F5 1 Tf .7126 0 TD (0.001.)Tj /F4 1 Tf 8.9663 0 0 8.9663 304.611 34.2425 Tm (4)Tj ET endstream endobj 62 0 obj <>stream /GS1 gs BT /F5 1 Tf 9.843 0 0 9.843 59.7543 452.1259 Tm 0 0 0 rg 0 Tc 0 Tw [(and)-304(18%84%)-303.6(for)-302.7(hydrochlorothiazide,)-306(respectively.)-309.5(Statis-)]TJ 0 -1.1116 TD [(tically)-540.4(signi辌ant)-543.3(preventive)-544.6(effects)-541(on)-537.8(zebra辳h)-541.8(venous)]TJ T* [(congestion)-347.5(were)-341.6(observ)-7.5(ed)-337.4(for)-343.1(LCZ696,)-347.5(digoxin,)-339.7(irbesartan,)]TJ 0 -1.1174 TD [(metoprolol,)-426.1(qiliqiangxin)-424(capsule,)-429.3(enalapril,)-426.1(shenmai)-425.9(injec-)]TJ 0 -1.1116 TD [(tion,)-284.6(and)-280.9(hydrochlorothiazide)-285.2(\(Table)-280.9(1)-283.3(and)-280.9(Fig.)-283.2(4\).)]TJ 1.0137 -1.1116 TD [(The)-259.1(increase)-261(in%)-252.2(of)-255.6(blood)-259.1(遫w)-257.4(velocity)-253.4(was)-258.6(6%66%)-256.4(for)]TJ -1.0137 -1.1116 TD [(LCZ696,)-330.3(11%30%)-332.4(for)-325.8(digoxin,)]TJ /F8 1 Tf 13.6044 0 TD (-)Tj /F5 1 Tf .5529 0 TD [(1%)-331.6(to)-324.9(1%)-331.6(for)-325.8(irbesartan,)]TJ -14.1574 -1.1174 TD [(0%29%)-314(for)-308.5(metoprolol,)-311(1%66%)-308.3(for)-308.5(qiliqiangxin)-314.5(capsule,)]TJ 0 -1.1116 TD [(1%42%)-256.4(for)-256.7(enalapril,)-264.9(19%35%)-251.8(for)-256.7(shenmai)-258.9(injection,)-258.1(and)]TJ T* [(5%53%)-319.8(for)-320(hydrochlorothiazide,)-323.2(respectively.)-321(Statistically)]TJ 0 -1.1174 TD [(signi辌ant)-238(preventive)-239.4(effects)-241.5(on)-232.6(zebra辳h)-236.5(venous)-238(congestion)]TJ 0 -1.1116 TD [(were)-295.6(observed)-293.1(for)-291.2(LCZ696,)-289.9(digoxin,)-287.9(irbesartan,)-294.4(metoprolol,)]TJ T* [(qiliqiangxin)-424(capsule,)-423.5(enalapril,)-420.4(shenmai)-420.1(injection,)-419.4(and)-419.2(hy-)]TJ 0 -1.1174 TD [(drochlorothiazide)-288.8(\(Table)-280.9(1)-283.3(and)-280.9(Fig.)-277.4(5\).)]TJ /F4 1 Tf 8.9663 0 0 8.9663 59.7543 281.2535 Tm (Discussion)Tj /F5 1 Tf 9.843 0 0 9.843 69.7323 264.8125 Tm [(This)-305(study)-299.2(aimed)-302.9(to)-301.8(develop)-303.9(and)-298.2(validate)-306.4(a)-301.8(live)-299.6(zebra辳h)]TJ -1.0137 -1.1174 TD [(heart)-336.2(failure)-338.5(model)-330.6(for)-331.5(rapid)]TJ /F7 1 Tf 12.0378 0 TD [(in)-330.6(vivo)]TJ /F5 1 Tf 3.1218 0 TD [(screening)-335.8(and)-332.8(ef辌acy)]TJ -15.1595 -1.1116 TD [(assessment)-435.5(of)-428.4(heart)-428.4(failure)-430.7(therapeutic)-431.8(drugs.)-423.4(Zebra辳h)-432.4(is)]TJ T* [(emerging)-214.1(as)-210.5(a)-209.6(predictive)-210.7(animal)-212(model)-209.6(for)]TJ /F7 1 Tf 16.9681 0 TD [(in)-209.7(vivo)]TJ /F5 1 Tf 2.8799 0 TD (assessment)Tj -19.8479 -1.1174 TD [(of)-203.8(drug)-206(ef辌acy,)-205.7(toxicity,)-204(and)-200.3(safety.)]TJ 7.3823 0 0 6.5614 202.7338 225.3543 Tm (21,2427)Tj 9.843 0 0 9.843 232.4409 220.9322 Tm [(We)-207.2(use)-200.1(zebra辳h)]TJ -17.5441 -1.1116 TD [(because)-363.5(of)-353.5(their)-358.2(many)-358.1(advantages)-355.4(such)-356.7(as)-360.3(short)-356.8(generation)]TJ T* [(times,)-282.1(amenability)-288.1(for)-279.7(large-scale)-282.9(screening,)-281.7(high)-281(fecundity,)]TJ 0 -1.1174 TD [(ease)-307.2(of)]TJ /F7 1 Tf 3.1678 0 TD [(in)-307.6(vitro)]TJ /F5 1 Tf 3.283 0 TD [(fertilization,)-309.9(and)-304(transparency.)]TJ 7.3823 0 0 6.5614 245.0834 192.4724 Tm (2830)Tj 9.843 0 0 9.843 266.57 188.0503 Tm (Another)Tj -21.0114 -1.1116 TD [(important)-329.4(advantage)-331.5(of)-324.7(the)-332.9(zebra辳h)-328.7(as)-325.7(an)-325.9(animal)-333(model)-324.8(is)]TJ T* [(that)-391.7(the)-390.5(morphological)-392.6(and)-390.4(molecular)-395(bases)-393.3(of)-388.1(tissues)-388.7(and)]TJ T* [(organs)-445.3(are)-437.6(either)-441.1(identical)-445.9(or)-434.1(similar)-442.2(to)-440.1(other)-438.7(vertebrates,)]TJ 0 -1.1174 TD [(including)-282.2(humans.)]TJ 7.3823 0 0 6.5614 133.0015 148.5921 Tm (22,31)Tj 9.843 0 0 9.843 69.7323 133.285 Tm [(In)-376.5(this)-378.8(study,)-377.5(we)-378.6(have)-381.1(selected)-382.1(verapamil)-377.7(to)-376.7(treat)-382.4(larval)]TJ -1.0137 -1.1116 TD [(zebra辳h)-369(at)-366.4(an)-366.2(optimum)-367.5(developmental)-366.2(stage)-370.6(of)-365(2)-364(dpf)-360.4(and)]TJ 0 -1.1174 TD [(optimized)-353.7(verapamil)-348.9(treatment)-349.1(concentration)-347.6(and)-350(treatment)]TJ 0 -1.1116 TD [(time)-364.2(period)-365(to)-365.2(develop)-361.5(a)-365.1(live)-362.9(zebra辳h)-363.3(heart)-365(failure)-367.3(model)]TJ T* [(with)-408.7(quantitative)-409(analysis.)-411.9(Zebra辳h)-409.4(at)-406.7(2)-404.3(dpf)-406.5(were)-410.7(treated)]TJ 0 -1.1174 TD [(with)-195.6(verapamil)-199.2(at)-193.6(a)-198.1(concentration)-197.9(of)-192.2(200)]TJ /F6 1 Tf 16.1157 0 TD (l)Tj /F5 1 Tf .5472 0 TD [(M)-197.8(for)-193.3(a)-192.3(time)-197.1(period)]TJ -16.6628 -1.1116 TD [(of)-221(30)-169.2(min,)-221.2(which)-220.8(were)-220.7(determined)-223.3(as)-222(optimum)-223.5(conditions)-219.7(for)]TJ T* [(zebra辳h)-351.7(heart)-342(failure)-350(model)-342.1(development.)-348.8(Heart)-348.6(dilatation)]TJ 25.5097 40.1855 TD [(and)-424.9(venous)-428(congestion)-428.1(in)-428.5(the)-425.1(live)-426.3(zebra辳h)-426.6(were)-433.8(visually)]TJ 0 -1.1116 TD [(tracked)-305(and)-304(con農med)-300.2(under)-306.1(a)-301.8(dissecting)-307.1(stereomicroscope.)]TJ T* [(Th)19.6(e)-209.6(c)0(a)12.8(r)0(d)20.9(i)0(a)19.6(c)-209.6(ou)15.1(tp)20.7(ut)-203.9(an)19.7(d)-208.4(b)0(l)14.9(o)0(o)20.8(d)-208.4(遫)15.2(w)-209.3(d)0(y)20.8(n)0(a)19.7(m)0(i)19.5(c)0(s)-204.8(o)0(f)-203.8(z)0(e)18.5(b)0(r)20.9(a)0()19.8(s)0(h)-203.6(w)0(e)18.8(r)0(e)]TJ 0 -1.1174 TD [(su)21(bj)20.7(ec)18.5(te)19.5(d)-404.3(t)0(o)-394(v)0(i)14.9(d)0(e)19.7(o)-404.3(re)19.7(co)19.7(rd)20.9(in)20.7(g)-404.3(u)0(n)15.1(d)0(e)19.7(r)-404.3(a)-405.4(Z)0(e)18.5(b)0(r)20.9(a)0(l)19.6(a)0(b)-395(B)0(l)19.7(o)0(o)20.8(d)-404.3(Fl)20.9(ow)]TJ 0 -1.1116 TD [(Sy)21(st)20.9(em)18.5(.)-228.1(W)0(e)-224.5(f)0(o)20.9(u)0(n)20.8(d)-231.5(th)20.7(at)-222.4(la)19.6(rv)20.9(al)-222.4(ze)18.5(br)20.9(a)19.8(sh)-220.9(tr)20.7(ea)18.5(te)19.6(d)-231.5(w)0(i)19.8(t)0(h)-221.2(v)0(e)19.7(r)0(a)19.7(p)0(a)19.7(m)0(i)19.5(l)]TJ T* [(un)20.8(de)19.7(r)-260.3(t)0(h)20.7(e)0(s)19.9(e)-255.7(op)20.8(ti)14.8(mu)19.6(m)-255.7(c)0(o)19.7(n)0(d)20.8(i)0(t)20.6(i)0(o)15(n)0(s)-243.9(d)0(e)19.7(v)0(e)19.7(l)0(o)15(p)0(e)19.7(d)-254.5(pe)19.7(ri)15(ca)18.5(rd)20.9(ia)19.6(l)-254.7(e)0(d)13.9(e)0(m)18.4(a)]TJ T* [(an)19.7(d)-243(v)0(e)19.7(n)0(o)20.8(u)0(s)-232.4(b)0(l)20.7(o)0(o)20.8(d)-243(co)19.7(ng)20.8(es)19.9(ti)20.6(on)-232.6(wi)19.8(th)-232.7(re)19.7(du)20.8(ce)12.8(d)-237.2(c)0(a)18.5(r)0(d)20.9(i)0(a)13.8(c)-238.4(ou)20.8(tp)14.9(ut)-227(an)19.7(d)]TJ 0 -1.1174 TD [(bl)20.7(oo)20.8(d)-300.6()0(o)21(w)-301.5(ve)19.7(lo)20.7(ci)19.6(ty)20.7(,)-302.9(s)0(i)20.9(m)0(i)19.5(l)0(a)19.6(r)-300.6(to)-290.3(th)20.7(e)-301.8(p)0(a)19.7(t)0(h)20.7(o)0(p)20.8(h)0(y)20.8(s)0(i)15.1(o)0(l)20.7(o)0(g)20.8(y)-300.6(ob)20.8(se)19.9(rv)20.9(ed)]TJ 0 -1.1116 TD [(in)-405.5(hu)20.8(ma)18.5(n)-415.8(h)0(e)19.7(a)0(r)14(t)-415.9(fa)19.7(il)20.6(ur)20.9(e)-417(p)0(a)19.7(t)0(i)14.8(e)0(n)19.7(t)0(s)20.9(,)]TJ 7.3823 0 0 6.5614 438.2928 368.844 Tm -.0162 Tc (32)Tj 9.843 0 0 9.843 449.688 364.4787 Tm 0 Tc [(in)20.7(di)20.7(ca)18.5(ti)20.6(ng)-411.1(th)20.7(at)-406.7(ve)19.7(ra)19.7(pa)19.7(mi)19.5(l)]TJ -14.1055 -1.1116 TD [(co)19.7(ul)20.7(d)-358.2(i)0(n)20.7(d)0(u)20.8(c)0(e)-350.1(h)0(e)19.7(a)0(r)19.7(t)-352.6(fa)14(il)20.6(ur)20.9(e)-353.6(i)0(n)-347.9(l)0(a)19.5(r)0(v)20.9(a)0(l)-349.1(z)0(e)18.5(b)0(r)20.9(a)0()14.1(s)0(h)21(.)-354.8(Th)19.6(is)-347.7(ze)18.5(br)20.9(a)19.8(sh)]TJ 0 -1.1174 TD [(he)19.7(ar)19.7(t)-254.7(f)0(a)13.9(i)0(l)20.6(u)0(r)20.9(e)-255.7(mo)19.6(de)19.7(l)-260.4(i)0(s)-244(s)0(t)20.9(a)0(b)19.7(l)0(e)-251.2(a)0(n)19.7(d)-254.5(hi)20.7(gh)20.8(ly)-250(re)19.7(pr)20.9(od)20.8(uc)19.7(ib)14.9(le)-245.4(wi)19.8(th)-244.2(CV)]TJ 0 -1.1116 TD [(va)19.7(lu)20.7(es)-308.4(of)-307.4(in)15(tr)20.7(ae)18.5(xp)20.8(er)19.7(im)19.5(en)13.9(ts)20.9(,)-314.5(i)0(n)15(t)0(e)19.5(r)0(e)19.7(x)0(p)20.8(e)0(r)19.7(i)0(m)19.5(e)0(n)13.9(t)0(s)20.9(,)-314.5(an)13.9(d)-317.9(d)0(a)19.7(y)0(-)20.9(t)0(o)20.7(-)0(d)20.9(a)0(y)]TJ T* [(va)19.7(ri)20.7(at)19.5(io)14.9(ns)]TJ /F8 1 Tf 4.1355 0 TD ()Tj /F5 1 Tf .5472 0 TD [(25)20.8(%)-267.1(\()0(d)15.1(a)0(t)19.5(a)-267.2(no)15.1(t)-266.2(s)0(h)21(o)0(w)14.2(n)0(\))20.9(.)]TJ -3.6689 -1.1174 TD [(Our)-482.2(辬dings)-491.3(were)-485.6(supported)-489(by)-486(an)-487.2(earlier)-489.4(preliminary)]TJ -1.0137 -1.1116 TD 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[(National)-334.9(Key)-327.9(Science)-329.1(and)-327(Technology)-331.5(Project)-326.9(Grant)-330.2(of)-330.5(the)]TJ T* [(12th)-281(5-year)-285.3(program)-280.7(of)-284.4(China)-278.5(\(2011ZX09301-003\).)]TJ /F4 1 Tf 8.9663 0 0 8.9663 313.0582 523.7857 Tm [(Disclosure)-336.7(Statement)]TJ /F5 1 Tf 9.843 0 0 9.843 323.0361 507.3448 Tm [(No)-279.5(competing)-284.4(辬ancial)-283.1(interests)-288.7(exist.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 313.0582 480.5857 Tm (References)Tj /F5 1 Tf 9.2951 0 0 9.2951 317.707 464.5416 Tm [(1.)-500.4(The)-329.8(American)-327.7(Heart)-329.6(Association)-331.4(Statistics)-331.4(Committee)-329.1(and)]TJ 1.2503 -1.1284 TD [(Stroke)-442.8(Statistics)-441.2(Subcommittee:)-441.2(Heart)-445.5(disease)-438.2(and)-443.8(stroke)]TJ 0 -1.1223 TD [(statistics-2012)-440.4(update:)-429.1(a)-431.3(report)-436.1(from)-431.7(the)-431(American)-437.5(Heart)]TJ 0 -1.1284 TD [(Association.)-337.5(Circulation)-338.1(2012;125:e2衑220.)]TJ -1.2503 -1.1223 TD 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-1.1284 TD [(5.)-500.4(De)18.3(lg)18.6(ad)19.9(o)-183.1(D)0(R)17.8(,)-176.9(Na)18.3(wa)18.3(r)-179.3(M)0(A)17.2(,)-176.9(Ze)18(wa)18.3(il)-169.9(AM)17.2(,)]TJ /F7 1 Tf 16.3154 0 TD [(et)-174.7(al)18.6(.)]TJ /F5 1 Tf 2.092 0 TD [(Cy)19.3(cl)20.5(oo)18(xy)18(ge)19.9(na)19.9(se)20.8(-)]TJ -17.1572 -1.1223 TD [(2)-353.9(i)12.6(nh)18(i)12.6(b)0(i)18.6(t)0(o)18.6(r)-350.1(t)12.6(r)0(e)17.6(a)0(t)20.5(m)0(e)14.2(n)0(t)-335.2(i)0(m)19(p)0(r)15.7(o)0(v)24.1(e)0(s)-339.1(l)0(e)14.4(f)0(t)-337.5(v)0(e)19.9(n)0(t)18.6(r)0(i)16.3(c)14(ul)18.6(ar)-342.3(fu)21.8(nc)19.9(ti)19.2(on)-341.8(an)19.9(d)]TJ 0 -1.1284 TD [(mo)18.4(rt)16.3(a)14(l)0(i)19.2(t)0(y)-408.4(i)0(n)-408.4(a)-419.1(m)12.5(u)0(r)21.8(i)0(n)18.6(e)-419.1(m)12.5(o)0(d)18(e)0(l)-406.5(o)0(f)-405.2(d)0(o)18(x)0(o)18(r)0(u)21.8(b)0(i)18.6(c)0(i)20.5(n)0(-)15.7(i)12.6(nd)18(uc)19.9(ed)-407(he)19.9(ar)17.6(t)]TJ 0 -1.1223 TD [(fa)17.6(il)19.2(ur)15.7(e)14(.)-262.3(Ci)19.9(rc)17.6(ul)18.6(a)14(t)0(i)19.2(o)0(n)-250.4(2)0(0)18(0)0(4)18(;)12.6(10)18(9:)18.6(14)24.1(28)18(1)18(43)24.1(3.)]TJ -1.2503 -1.1284 TD [(6.)-500.4(Zon)-411(LI,)-413.2(Peterson)-409.8(RT.)-415.7(In)-405.2(vivo)-414.7(drug)-411.5(discovery)-407(in)-414.5(the)-406.6(zeb-)]TJ 1.2503 -1.1223 TD [(ra辳h.)-338.7(Nat)-335(Rev)-332.7(Drug)-333.8(Dis)-336(2005;4:3544.)]TJ -1.2503 -1.1284 TD [(7.)-500.4(Jeroen)-395(B.)-389.2(Zebra辳h)-393.9(as)-387.9(a)-394.7(model)-388.2(to)-390.1(study)-389.6(cardiac)-391.6(develop-)]TJ 1.2503 -1.1223 TD [(ment)-314.8(and)-309.6(human)-309.5(cardiac)-312.4(disease.)-310.2(Cardiovasc)-312.5(Res)-313.5(2011;91:)]TJ 0 -1.1284 TD (279288.)Tj -1.2503 -1.1223 TD [(8.)-500.4(Hecker)-200.4(L,)-191.2(Khait)-194.4(L,)-191.2(Sessions)-194.1(S)-192.1(K)0(,)]TJ /F7 1 Tf 14.4125 0 TD [(et)-193(al.)]TJ /F5 1 Tf 2.1408 0 TD [(Functional)-194(evalsuation)]TJ -15.303 -1.1284 TD [(of)-271(isolated)-275.3(zebra辳h)-274.3(hearts.)-272.5(Zebra辳h)-272(2008;5:319322.)]TJ -1.2503 -1.1223 TD [(9.)-500.4(Langheinrich)-407.8(U,)-398.2(Vacun)-401.1(G,)-404.3(Wagner)-400.2(T.)-398.5(Zebra辳h)-406.1(embryos)]TJ 1.2503 -1.1284 TD [(express)-308.8(an)-303.3(orthologue)-299.6(of)-301.5(HERG)-303.2(and)-303.5(are)-303.9(sensitive)-305.1(toward)-307.3(a)]TJ 0 -1.1223 TD [(range)-322.5(of)-313.7(QT-prolonging)-319.9(drugs)-319.3(inducing)-321.4(severe)-319.9(arrhythmia.)]TJ 0 -1.1284 TD [(Toxicol)-335.3(Appl)-337(Pharmacol)-335.3(2003;193:370382.)]TJ -1.7505 -1.1284 TD [(10.)-500.5(Hassel)-423.3(D,)-422.6(Scholz)-420.3(EP,)-419.9(Trano)-423.9(N,)]TJ /F7 1 Tf 15.4189 0 TD [(et)-418.7(al.)]TJ /F5 1 Tf 2.5983 0 TD [(De辌ient)-419.7(zebra辳h)]TJ -16.2667 -1.1223 TD (Ether-a)Tj 2.5739 .0427 TD (`)Tj .3843 -.0427 TD [(-Go-Go衦elated)-444.5(gene)-442(channel)-440(gating)-443.1(causes)-438.7(short-)]TJ -2.9581 -1.1284 TD [(QT)-613.7(syndrome)-616.3(in)-609.6(zebra辳h)-615.8(reggae)-619.6(mutants.)-612.8(Circulation)]TJ 0 -1.1223 TD (2008;117:866.)Tj -1.7505 -1.1284 TD [(11.)-500.5(Verkerk)-332.8(AO,)-326.8(Remme)-324.1(CA.)-330(Zebra辳h:)-326.4(a)-327.6(novel)-321.5(research)-332.8(tool)]TJ 1.7505 -1.1223 TD [(for)-413.7(cardiac)-416(\(patho\)electrophysiology)-413.9(and)-413.3(ion)-408.5(channel)-415.6(dis-)]TJ 0 -1.1284 TD [(orders.)-338.3(Front)-334.7(Physiol)-331.2(2012;3:255.)]TJ -1.7505 -1.1223 TD [(12.)-500.5(Mi)19.3(la)14.4(n)-372.2(D)0(J)17.3(,)-372.1(Ki)17(m)-371.8(A)0(M)17.2(,)-372.1(Wi)20.3(nt)18.6(er)17.6(辝)23.1(ld)-365.7(JR)20.2(,)]TJ /F7 1 Tf 17.0474 0 TD [(e)14(t)-377.7(al)18.6(.)]TJ /F5 1 Tf 2.4763 0 TD [(Dr)20.2(ug)18(-s)22.7(en)19.9(si)19.5(ti)19.2(ze)15.7(d)]TJ -17.7732 -1.1284 TD [(ze)15.7(br)21.8(a)17(sh)-292.2(sc)14.7(re)23.7(en)-297.3(i)12.6(d)0(e)13.8(n)0(t)24.7(i)0()15.7(e)0(s)-290.3(m)0(u)18.4(l)0(t)19.2(i)0(p)18.6(l)12.6(e)-309.3(g)0(e)19.9(n)0(e)19.9(s)12.9(,)-305(i)0(n)18.6(c)0(l)20.5(u)0(d)18(i)12.6(ng)-293(GI)14.1(NS)19.6(3,)]TJ 0 -1.1223 TD [(as)-265.9(re)23.7(gu)18(la)20.5(to)18.6(rs)-264(of)-258.8(m)12.5(y)0(o)18(c)0(a)15.7(r)0(d)21.8(i)0(a)20.5(l)-274(re)17.6(po)24.1(la)20.5(ri)16.3(za)15.7(t)12.6(i)0(o)18.6(n)0(.)-256.4(C)0(i)13.8(r)0(c)23.7(u)0(l)18.6(a)0(t)20.5(i)0(o)18.6(n)-274.6(20)24.1(09)18(;)]TJ 0 -1.1284 TD [(12)18(0:)18.6(55)18(3.)]TJ -1.7505 -1.1223 TD [(13.)-500.5(Gu)-386.1(G,)-386(Na)-390.3(Y,)-386(Chung)-383.7(H,)]TJ /F7 1 Tf 12.0216 0 TD [(et)-388.2(al.)]TJ /F5 1 Tf 2.5312 0 TD [(Zebra辳h)-387.8(Larvae)-389.8(Model)-381.8(of)]TJ -12.8023 -1.1284 TD [(Dilated)-405.7(Cardiomyopathy)-400.2(Induced)-402.1(by)-396.7(Terfenadine.)-408.7(Korean)]TJ 0 -1.1223 TD [(Circ)-340.7(J)-328.6(2017;47:960969.)]TJ /F4 1 Tf 8.9663 0 0 8.9663 62.022 749.6502 Tm (10)Tj 49.0531 0 TD [(ZHU)-333.7(ET)-338.7(AL.)]TJ ET endstream endobj 92 0 obj <>stream /GS1 gs BT /F5 1 Tf 9.2951 0 0 9.2951 59.7543 725.1588 Tm 0 0 0 rg 0 Tc 0 Tw [(14.)-500.5(Shi)-387(X,)-379.9(Verma)-390.8(S,)-381.3(Yun)-380.2(J,)]TJ /F7 1 Tf 12.2351 0 TD [(et)-388.2(al.)]TJ /F5 1 Tf 2.5312 0 TD [(Effect)-387.3(of)-380.8(empagli遫zin)-387.2(on)]TJ -13.0158 -1.1223 TD [(cardiac)-440.4(biomarkers)-433.5(in)-432.8(a)-431.3(zebra辳h)-432.9(model)-437(of)-429.6(heart)-431.7(failure:)]TJ 0 -1.1284 TD [(clues)-605.4(to)-597.4(the)-601.8(EMPA-REG)-602.9(OUTCOME)-599.1(trial?.)-601.6(Mol)-602.9(Cell)]TJ 0 -1.1223 TD [(Biochem)-336.5(2017;433:97102.)]TJ -1.7505 -1.1283 TD [(15.)-500.5(Kim)-342.6(JY,)-336.5(Kim)-336.5(HH,)-339(Cho)-334.6(KH.)-339(Acute)-339.5(cardiovascular)-342.8(toxicity)]TJ 1.7505 -1.1223 TD [(of)-496.6(sterilizers,)-496.7(PHMG,)-493.9(and)-492.6(PGH:)-494(severe)-490.7(in遖mmation)-498.3(in)]TJ 0 -1.1284 TD [(human)-596.1(cells)-598.7(and)-596.3(heart)-596.4(failure)-598.4(in)-591.3(zebra辳h.)-597.6(Cardiovasc)]TJ 0 -1.1223 TD [(Toxicol)-335.3(2013;13:148160.)]TJ -1.7505 -1.1284 TD -.0192 Tc [(1)-19.2(6)-19.2(.)-519.7(Huan)5.1(g)-482.9(CC,)-476.7(Mon)5.1(t)-.5(e)-481(A)-2.6(,)-476.7(C).3(oo)5.1(k)-482.9(J)-.2(M)5.8(,)-482.8(Kabir)-479.1(M)-.3(S,)-476.7(Peterson)-476.8(KP.)]TJ 1.7505 -1.1223 TD -.0188 Tc [(Zebra辳h)-330(heart)-329.4(f)3.1(ai)6(lure)-328.1(models)-323(fo)5.5(r)-332.3(t)6(he)-328.1(evalsuatio)5.5(n)-330(o)-.6(f)-326.2(c)1.3(hemi)6(cal)]TJ 0 -1.1284 TD [(probes)-231.5(a)1.3(n)5.5(d)-232.4(drug)5.5(s.)-232.3(Assay)-232.4(D)3.9(rug)-232.4(D)3.9(ev)-232.4(Tech)5.5(nol)-225.7(201)5.5(3;1)5.5(1)-.6(:56)5.5(157)5.5(2.)]TJ -1.7505 -1.1223 TD 0 Tc [(17.)-500.5(Huang)-317.6(CC,)-321(Chen)-320.6(PC,)-313(Huang)-317.6(CW,)-320.6(Yu)-319(J.)-316.5(Aristolochic)-321.9(Acid)]TJ 1.7505 -1.1284 TD [(induces)-325.1(heart)-321.9(failure)-324(in)-323(zebra辳h)-323.1(embryos)-323.4(that)-320.8(is)-322.1(mediated)]TJ T* [(by)-335.7(in遖mmation.)-333.7(Toxicol)-335.3(Sci)-336.3(2007;100:486.)]TJ -1.7505 -1.1223 TD [(18.)-500.5(Kimmel)-693.9(CB,)-686.9(Ballard)-686.3(WW,)-692.2(Kimmel)-687.8(SR,)-685.1(Ullmann)-694.4(B,)]TJ 1.7505 -1.1284 TD [(Schilling)-567.2(TF.)-566.3(Stages)-565.7(of)-563.7(embryonic)-566.1(development)-561.6(of)-563.7(the)]TJ 0 -1.1223 TD [(zebra辳h.)-341.4(Dev)-329.5(Dynam)-335.4(1995;203:253310.)]TJ -1.7505 -1.1284 TD [(19.)-500.5(Zhou)-344(J,)-340.9(Xu)-343.4(YQ,)-345.1(Guo)-337.5(SY,)-346.4(Li)-337.1(CQ.)-348.3(Rapid)-338.5(analysis)-348.2(of)-338.1(hypo-)]TJ 1.7505 -1.1223 TD [(lipidemic)-568.1(drugs)-563.3(in)-566.9(a)-559.4(live)-564.8(zebra辳h)-567(assay.)-568.6(J)-560.4(Pharmacol)]TJ 0 -1.1284 TD [(Toxicol)-335.3(Methods)-338.5(2015;72:4752.)]TJ -1.7505 -1.1223 TD [(20.)-500.5(Listed)-340.4(N.)-331.2(Biomarkers,)-340.7(genomics,)-337.1(telemetry,)-337.4(computational)]TJ 1.7505 -1.1284 TD [(biology,)-262.2(and)-260.8(zebra辳h:)-261.7(will)-262.7(one)-260.8(of)-258.8(these)-263.8(solve)-259.6(the)-266.3(problems)]TJ 0 -1.1223 TD [(of)-478.3(post-myocardial)-473.9(infarction)-482.4(heart)-474.4(failure?.)-474.8(Eur)-480.4(Heart)-476(J)]TJ 0 -1.1284 TD (2014;35:5758.)Tj -1.7505 -1.1223 TD [(21.)-500.5(Zhu)-386.6(XY,)-387.8(Liu)-386(HC,)-391(Guo)-386.3(SY,)]TJ /F7 1 Tf 13.6379 0 TD [(et)-388.2(al.)]TJ /F5 1 Tf 2.5373 0 TD [(A)-386(zebra辳h)-390.2(thrombosis)]TJ -14.4247 -1.1284 TD [(model)-357.7(for)-358.8(assessing)-359.4(antithrombotic)-357.1(drugs.)-356(Zebra辳h)-357.3(2016;)]TJ 0 -1.1223 TD (13:335.)Tj -1.7505 -1.1284 TD [(22.)-500.5(McGrath)-378(P,)-381.3(Li)-373.7(CQ.)-378.8(Zebra辳h:)-375.2(A)-379.9(predictive)-380.6(model)-376(for)-377.1(as-)]TJ 1.7505 -1.1223 TD [(sessing)-386.2(drug-)-389.6(induced)-387(toxicity.)-387.4(Drug)-382.6(Discov)-389.4(Today)-385(2008;)]TJ 0 -1.1284 TD (13:394401.)Tj -1.7505 -1.1223 TD [(23.)-500.5(We)15.6(s)12.9(t)0(e)14.4(r)0()18.9(e)14(ld)-408.4(M:)-413.7(Th)22.2(e)-419.1(Z)0(e)18(b)0(r)21.8(a)0()17(s)12.9(h)-421(B)0(o)19.3(o)0(k)18(:)-414.3(A)-422.6(G)0(u)22.5(i)0(d)18.6(e)-419.1(fo)21.8(r)-423.3(t)12.6(he)-407(La)18(-)]TJ 1.7505 -1.1284 TD [(bo)18(ra)17.6(t)12.6(o)0(r)15.7(y)-170.9(Us)23.4(e)-175.1(o)0(f)-161.2(Z)0(e)24.1(b)0(r)15.7(a)0()23.1(s)0(h)-164.1(\()]TJ /F7 1 Tf 10.3992 0 TD [(Da)22.5(ni)18.6(o)-170.9(r)0(e)14.7(r)12.9(io)]TJ /F5 1 Tf 4.5805 0 TD [(\).)-161.1(Un)22.5(iv)18.6(er)17.6(si)19.5(t)12.6(y)-170.9(of)-161.2(Or)20.2(eg)13.8(on)]TJ -14.9797 -1.1223 TD [(Eu)16.1(ge)19.9(ne)-248.5(OR)-250.6(Pr)18.9(es)14.7(s)12.9(,)-262.3(Or)20.2(eg)19.9(on)18(,)-256.2(1)0(9)18(9)0(9)18(.)]TJ -1.7505 -1.1284 TD [(24.)-500.5(Zhu)-289(JJ,)-291.4(Xu)-288.5(YQ,)-296.3(He)-286.6(JH,)]TJ /F7 1 Tf 11.552 0 TD [(et)-290.6(al.)]TJ /F5 1 Tf 2.336 0 TD [(Human)-292.7(cardiotoxic)-295.4(drugs)-288.8(de-)]TJ -12.1375 -1.1223 TD [(livered)-205.8(by)-207.7(soaking)-205(and)-205.9(microinjection)-208.8(induce)-203.9(cardiovascular)]TJ 0 -1.1284 TD [(toxicity)-271.4(in)-274.2(zebra辳h.)-274.4(J)-267.6(Appl)-270(Toxicol)-274.3(2013;34:139148.)]TJ -1.7505 -1.1223 TD [(25.)-500.5(Zhou)-270.8(J,)-267.7(Guo)-270.4(SY,)-267.1(Zhang)-269.1(Y,)-270.2(Li)-270(CQ.)-269(Human)-268.3(prokinetic)-272.7(drugs)]TJ 1.7505 -1.1284 TD [(promote)-500.6(gastrointestinal)-506.1(motility)-498(in)-499.8(zebra辳h.)-506.1(Neurogas-)]TJ 0 -1.1223 TD [(troenterol)-336(Motil)-333.7(2014;26:589595.)]TJ -1.7505 -1.1284 TD [(26.)-500.5(Yang)-427.2(R,)-419.7(Lao)-427.4(QC,)-421.5(Yu)-422.7(HP,)]TJ /F7 1 Tf 13.3085 0 TD [(et)-424.8(al.)]TJ /F5 1 Tf 2.6044 0 TD [(Tween-80)-424(and)-425.5(impurity)]TJ -14.1624 -1.1223 TD [(induce)-325.9(anaphylactoid)-328.1(reaction)-326(in)-329.1(zebra辳h.)-323.2(J)-328.6(Appl)-324.8(Toxicol)]TJ 0 -1.1284 TD (2015;35:295301.)Tj -1.7505 -1.1223 TD [(27.)-500.5(He)-396.4(JH,)-391.4(Gao)-396.6(JM,)-389.1(Huang)-396.9(CJ,)-394.6(Li)-392(CQ.)-391(Zebra辳h)-400(models)-393.5(for)]TJ 1.7505 -1.1284 TD [(assessing)-505.7(developmental)-504.5(and)-498.7(reproductive)-499.7(toxicity.)-503.3(Neu-)]TJ 0 -1.1223 TD [(rotoxicol)-335.5(Teratol)-335.7(2014;42:3542.)]TJ -1.7505 -1.1284 TD [(28.)-500.5(Weyand)-397.9(AC,)-397.1(Shavit)-397.2(JA.)-397.5(Zebra辳h)-400(as)-394(a)-394.7(model)-400.4(system)-398.7(for)]TJ 1.7505 -1.1284 TD [(the)-241.9(study)-237.1(of)-240.5(hemostasis)-243.5(and)-242.5(thrombosis.)-238.4(Curr)-241.8(Opin)-239.5(Hematol)]TJ 0 -1.1223 TD (2014;21:418422.)Tj -1.7505 -1.1284 TD [(29.)-500.5(Li)-355.4(C)13.4(Q)0(,)-349.5(L)0(u)16.1(o)-360(LQ)20.7(,)-359.9(A)0(w)14.9(e)0(r)17.6(m)12.5(an)-352.1(J)12.9(,)-359.9(Mc)14.5(Gr)20.2(at)20.5(h)-360(P)0(:)-350.3(W)0(h)19.8(o)0(l)18.6(e)-364.2(ze)21.8(br)15.7(a)14()0(s)16(h)]TJ 1.7505 -1.1223 TD [(cy)19.9(to)18.6(ch)19.9(ro)15.7(m)12.5(e)-370.3(P)15.3(4)0(5)18(0)-366.1(as)20.8(sa)14.7(y)-366.1(f)0(o)21.8(r)-368.4(as)20.8(se)20.8(ss)13.7(i)12.6(n)0(g)-354(d)0(r)15.7(u)0(g)-354(m)12.5(et)14.4(ab)19.9(ol)18.6(i)12.6(s)0(m)-358.8(a)0(n)19.9(d)]TJ 0 -1.1284 TD [(sa)14.7(fe)23.7(ty)18.6(.)-231.8(I)0(n)15.7(:)-231.3(Ze)18(br)21.8(a)17(s)12.9(h)0(:)-225.4(M)12.8(et)20.5(ho)18(ds)-225.1(fo)21.8(r)-228.1(A)0(s)17.3(s)0(e)14.7(s)12.9(si)19.5(ng)-219.9(Dr)14.1(ug)-219.9(Sa)17(fe)23.7(ty)-225.4(an)19.9(d)]TJ 0 -1.1223 TD [(To)16.1(xi)18.6(c)14(i)0(t)19.2(y)0(.)-463.8(P)0(.)-460.6(M)0(c)14.5(G)0(r)20.2(a)0(t)20.5(h)-475.9(\(e)23.7(d\))15.7(,)-469.7(p)0(p)18(.)0(1)18.1(0)0(3)24.1()0(1)18(1)0(5)18(,)-469.7(Wi)20.3(le)14.4(y-)21.8(Ba)21.2(lc)14.4(kw)22.5(el)20.5(l,)]TJ 0 -1.1284 TD [(We)15.6(s)12.9(t)-328.9(S)15.3(u)0(s)18.9(s)0(e)14.7(x)0(,)-311.3(U)0(K)21(,)-323.3(20)18(11)18(.)]TJ -1.7505 -1.1223 TD 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