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[(healthy)-304(volunteers)-295.6(received)-301.5(escalating)-303.8(doses)-294.3(of)-295.9(DX-2930)-297.4(or)]TJ
0 -1.1174 TD
[(placebo)-466.3(subcutaneously.)]TJ
7.3823 0 0 6.5614 411.6472 389.7637 Tm
(19)Tj
9.843 0 0 9.843 423.6093 385.3983 Tm
[(At)-458.2(higher)-462.9(doses,)-464.7(plasma)-465.1(levels)]TJ
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[(were)-364.7(judged)-359.2(sufcient)-363.5(to)-359.4(inhibit)-359.6(plasma)-361.4(kallikrein)-359.4(activity.)]TJ
T*
[(The)-305.2(half-life)-306.3(was)-298.9(1720)-299.3(days,)-302.6(suggesting)-305.8(infrequent)-301.5(admin-)]TJ
0 -1.1174 TD
[(istration)-299.4(would)-294.5(be)-297.1(required.)]TJ
7.3823 0 0 6.5614 423.4959 356.9385 Tm
(19)Tj
9.843 0 0 9.843 433.7574 352.5164 Tm
[(The)-299.4(most)-293.6(commonly)-294.8(reported)]TJ
-12.2624 -1.1116 TD
[(adverse)-229.8(effect)-229(was)-229.8(headache,)-231.2(but)-228.1(this)-223.3(was)-229.8(reported)-230.1(equally)-223.4(in)]TJ
T*
[(volunteers)-301.4(receiving)-301.6(DX-2930)-297.4(and)-298.2(placebo.)-297(Dyax,)-297.9(the)-298.3(man-)]TJ
T*
[(ufacturer,)-235.7(is)-226.8(performing)-226.6(a)-226.9(phase)-232.3(Ib)-226.8(study)-224.3(of)-226.8(administrat)-10.2(ion)-222.3(of)]TJ
0 -1.1174 TD
[(DX-2930)-262.9(in)-261.5(patients)-264.8(with)-259(HAE.)]TJ
7.3823 0 0 6.5614 439.0865 313.0582 Tm
[(19,2)-8.6(0)]TJ
/F4 1 Tf
9.9626 0 0 9.9626 313.0582 282.7275 Tm
[(Ant)-8(i-Facto)-10.1(r)-332(XIIa)-336.9(Ant)-8(ibody)]TJ
/F3 1 Tf
9.843 0 0 9.843 325.0204 264.8692 Tm
[(An)-458.1(alternative)-460.8(approach)-461.5(to)-451.6(preventing)-457.1(bradykinin)-461.7(gen-)]TJ
-1.2153 -1.1116 TD
[(eration)-390.4(and)-384.6(hence)-383.4(HAE)-386.4(attacks)-385.6(would)-386.6(be)-383.5(the)-384.7(inhibition)-380.3(of)]TJ
0 -1.1174 TD
[(activated)-274.1(Factor)-273.8(XII.)-266.7(Factor)-273.8(XII)-269.1(is)-267.1(typically)-271.9(thought)-272.9(to)-267.3(auto-)]TJ
0 -1.1116 TD
[(activate)-457.3(to)-445.8(Factor)-452.4(XIIa,)-447.5(which)-451.2(subsequently)-453.2(catalyzes)-453.5(the)]TJ
T*
[(conve)-7.8(rsion)-639(of)-641.5(prekallikrein)-651.8(to)-641.7(kallikrein.)-645.1(Kallikren)-647(can)]TJ
0 -1.1174 TD
[(then)-305.2(activate)-307.6(Factor)-302.6(XII)-297.9(leading)-304(to)-301.8(a)-301.8(positive)-303.9(feedback)-307.2(loop)]TJ
0 -1.1116 TD
[(and)-275.2(ultimately)-280.2(amplifying)-278.7(bradykinin)-271.6(generation.)]TJ
7.3823 0 0 6.5614 508.6487 203.4708 Tm
(21,22)Tj
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(While)Tj
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[(some)-242.8(recent)-246.3(data)-237.2(indicate)-243.1(prekallikrein)-248.7(can)-236(be)-245.3(auto-activated)]TJ
T*
[(to)-353.7(kallikrein)-353.6(or)-347.7(via)-355.9(the)-350.2(activity)-351.5(of)-353.5(other)-352.3(proteases,)]TJ
7.3823 0 0 6.5614 516.1321 181.5874 Tm
(23)Tj
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(Factor)Tj
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[(XIIa)-386.5(remains)-379.8(a)-382.4(potential)-381.4(target)-383.5(to)-376.7(prevent)-384.5(HAE)-380.6(attacks.)-383.3(A)]TJ
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[(monoclonal)-395(antibody)-390.4(against)-396(Factor)-389(XIIa)-392.3(was)-391(recently)-392.7(de-)]TJ
T*
[(scribe)-8.8(d.)]TJ
7.3823 0 0 6.5614 344.0692 148.7055 Tm
(24)Tj
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[(Its)-331.5(activity)-334.2(was)-333.5(investigated)-333.8(in)-330.6(a)-336.3(rabbit)-330.5(model)-330.6(of)]TJ
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[(extracorpor)-9.9(eal)-541.4(membrane)-538.9(oxygenation)-544.6(\(ECMO\),)-543.9(a)-537.9(thera-)]TJ
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[(peutic)-193.5(maneuver)-192.1(used)-189.7(in)-186.6(severe)-194.2(life-threatening)-195.6(lung)-188.8(injury.)]TJ
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(24)Tj
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[(The)-241.8(antibody)-234.9(signicantly)-240.3(decreased)-245.9(the)-235(incidence)-239.5(of)-238.3(throm-)]TJ
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[(bosis,)-400.3(a)-399.7(major)-399.7(complication)-404.4(of)-399.6(ECMO,)-403.5(without)-400.6(increasing)]TJ
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T*
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T*
[(co)13.9(ns)21(id)20.7(er)19.7(ed)19.7(.)-210.8(I)0(n)-203.8(a)0(d)19.7(d)0(i)20.7(t)0(i)20.6(o)0(n)15.1(,)-210.8(ot)20.7(he)19.7(r)-208.4(F)0(a)14.1(c)0(t)19.6(o)0(r)-198(X)0(I)20(I)0(a)-204.9(i)0(n)20.7(h)0(i)20.7(b)0(i)14.9(t)0(o)20.7(r)0(s)-197.8(h)0(a)13.9(v)0(e)-199.2(b)0(e)19.7(e)0(n)]TJ
/F4 1 Tf
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(178)Tj
48.4525 0 TD
(M)Tj
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(AC)Tj
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(GINNITIE)Tj
ET
endstream
endobj
35 0 obj
<>stream
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BT
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0 Tc
0 Tw
[(de)19.7(ve)13.9(lo)20.7(pe)19.7(d,)-246.4(bu)20.8(t)-260.4(t)0(h)20.7(e)0(i)19.5(r)-260.3(po)20.8(te)19.6(nt)14.9(ia)19.6(l)-260.4(u)0(s)21(e)-261.4(in)-244.2(HA)19.1(E)-261.5(w)0(o)20(u)0(l)20.7(d)-260.3(ap)19.7(pe)19.7(ar)-251(to)-250(be)]TJ
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0 Tc
(25)Tj
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[(Pot)-8.8(ential)-340.4(Adverse)-342.9(Effects)-338(of)-339.1(Kallikrei)-9.3(n)]TJ
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[(or)-338.3(Facto)-9.5(r)-332(XIIa)-336.9(Inhi)-8.2(bition)]TJ
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[(While)-446.9(inhibition)-443.6(of)-445.7(plasma)-447.8(kallikrein)-445.8(represents)-451.9(an)-441.1(at-)]TJ
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[(tractive)-461.9(target)-458.4(for)-458.3(treatment)-458.5(of)-457.2(HAE,)-458.9(there)-457.2(are)-460.6(little)-457.7(data)]TJ
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[(about)-352.4(the)-350.2(long-term)-352.3(safety)-354.4(of)-347.7(this)-350(approach.)-355.5(In)-347.7(healthy)-350.1(hu-)]TJ
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[(mans,)-367.1(bradykinin)-363.8(production)-363.8(occurs)-365.8(at)-366.4(low)-361.4(levels)-366.1(constitu-)]TJ
T*
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(22)Tj
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[(Bradykinin)-416.6(binds)-408.6(to)-405.5(two)-413.2(receptorsB1)-416.1(and)-407.6(B2with)-408.4(the)]TJ
T*
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T*
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T*
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(injury.)Tj
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(22)Tj
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[(In)-272.9(vitro)]TJ
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3.2773 0 TD
(and)Tj
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1.7222 0 TD
[(in)-278.8(vivo)]TJ
/F3 1 Tf
3.0123 0 TD
[(data)-277.6(ascribe)-276(a)-278.7(number)-273.9(of)-278.6(activ-)]TJ
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[(ities)-300.6(to)-296.1(bradykinin.)-298.1(These)-296.8(include)-298.3(vasodilation)-303.9(and)-292.4(resultant)]TJ
T*
[(decrease)-325.4(in)-313.3(blood)-316.7(pressure,)-319.4(as)-319.9(well)-317.7(as)-319.9(anti-proliferative)-318.9(and)]TJ
0 -1.1174 TD
[(both)-315.6(antithrombogenic)-316.6(and)-309.7(antibrinolytic)-318.9(activity.)]TJ
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(22)Tj
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[(All)-309.7(of)]TJ
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[(these)-220.9(activities)-228.1(can)-218.7(be)-216.5(detrimental)-224.7(or)-221(benecial)-222(depending)-219.7(on)]TJ
T*
[(the)-263.8(context.)]TJ
1.2153 -1.1174 TD
[(Mice)-485.8(decient)-478.9(in)-480.4(plasma)-482.4(kallikrein)-486.1(are)-477.9(phenotypically)]TJ
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(normal.)Tj
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(26)Tj
9.843 0 0 9.843 101.707 484.0439 Tm
[(They)-415.7(display)-417.9(prolonged)-414.4(activated)-418.1(partial)-419.3(throm-)]TJ
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[(boplastin)-385.7(time)-381.4(\(aPTT\),)-387.8(a)-382.4(marker)-384.5(of)-382.3(blood)-380(coagulation,)-382.3(but)]TJ
0 -1.1174 TD
[(are)-264.8(not)-256.9(at)-262.7(increased)-262.1(risk)-257.7(of)-261.4(bleeding.)-262.5(In)-255.6(fact,)-263.7(they)-259.1(seem)-261.2(to)-255.8(be)]TJ
0 -1.1116 TD
[(protected)-514.7(from)-506.7(both)-505.6(arterial)-508(and)-505.6(venous)-508.7(thrombosis,)-505.1(and)]TJ
T*
[(plasma)-396(kallikrein)-388.2(inhibition)-391.8(has)-390.2(been)-392.6(considered)-394.6(as)-389.1(a)-388.2(pos-)]TJ
T*
[(sible)-467.5(preventive)-464(therapy)-465.2(for)-464(thrombotic)-468.8(disorders)-465.8(such)-460.4(as)]TJ
0 -1.1174 TD
[(myocardial)-338.5(infarction)-336.2(and)-338.5(thrombotic)-336.3(stroke.)]TJ
7.3823 0 0 6.5614 240.0377 422.6456 Tm
(26)Tj
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[(Congenital)-371.9(plasma)-373(kallikrein)-370.9(inhibition)-368.8(has)-372.9(been)-369.6(identi-)]TJ
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[(ed)-263.5(in)-255.8(humans,)-259.9(where)-262.1(prekallikrein)-265.9(was)-258.6(historically)-263.6(referred)]TJ
0 -1.1174 TD
[(to)-555.3(as)-550.3()50.8(Fletcher)-554.8(factor)47.5()-554(based)-549(on)-549.4(the)-551.8(name)-555.1(of)-549.3(the)-551.8(rst)]TJ
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[(identied)-340.8(family)-331.8(with)-333.8(the)-332.9(deciency.)]TJ
7.3823 0 0 6.5614 208.7433 378.8219 Tm
(27)Tj
9.843 0 0 9.843 219.4015 374.4566 Tm
[(The)-339.7(index)-329.3(case)-336(was)]TJ
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[(identied)-409.9(due)-401.9(to)-405.5(a)-405.4(prolonged)-402.8(aPTT)-405.2(on)-405.4(routine)-406.5(presurgical)]TJ
0 -1.1174 TD
[(screening)-284(and,)-284.4(analogous)-282.9(to)-278.8(the)-281.1(mouse,)-281.8(no)-278.7(increased)-285.2(history)]TJ
0 -1.1116 TD
[(of)-411.1(bleeding.)]TJ
7.3823 0 0 6.5614 108.5102 345.9401 Tm
(27)Tj
9.843 0 0 9.843 119.9622 341.5747 Tm
[(Characterization)-342.9(of)-336.2(family)-337.5(members)-340.6(showed)]TJ
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[(three)-186.5(siblings)-187.4(with)-184.1(a)-186.6(similar)-183.1(phenotype.)-188.6(Patients)-184(with)-184.1(Fletcher)]TJ
T*
[(factor)-268.2(deciency)-268(appear)-263.5(to)-267.3(be)-262.5(healthy)-263.7(without)-262.4(increased)-267.9(risk)]TJ
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[(of)-261.4(thrombosis)-265.5(or)-261.4(bleeding.)]TJ
7.3823 0 0 6.5614 164.1826 313.0582 Tm
(27)Tj
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[(While)-360.5(both)-350.1(mice)-359.4(and)-355.8(humans)-354.4(lacking)-361.6(kallikrein)-353.6(activity)]TJ
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[(are)-547(without)-544.6(obvious)-537.5(defects)-546.8(and)-545.9(perhaps)-539.7(even)-548.1(protected)]TJ
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[(from)-310.8(thrombosis,)-303.5(the)-304.1(data)-312.1(available)-308.7(are)-305.1(limited,)-307.8(particularly)]TJ
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[(with)-339.6(respect)-339.4(to)-342.1(humans.)-334.8(While)-343.3(long-tern)-339.6(inhibition)-334.2(of)-342(plas-)]TJ
T*
[(ma)-379(kallikrein)-382.4(should)-375.2(prevent)-378.8(attacks)-379.9(of)-376.5(HAE)-380.6(without)-377.6(seri-)]TJ
0 -1.1174 TD
[(ous)-458.1(adverse)-466(effects)-460.3(and)-459.5(might)-462(even)-456(be)-458.4(protective)-464.1(against)]TJ
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[(thrombosis,)-315(the)-309.9(safety)-314.1(of)-313.2(such)-310.6(an)-308.6(approach)-317.5(in)-307.6(a)-313.3(large)-313.2(group)]TJ
T*
[(of)-295.9(patients)-224.4(with)-218.6(HAE)-225.1(remains)-218.5(unproven.)-226.5(Any)-217.3(adverse)-224.1(effects)]TJ
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[(might)-323.8(be)-320.1(signicantly)-326.7(more)-323.5(pronounced,)-322(with)-322.3(kallikrein)-324.9(in-)]TJ
0 -1.1116 TD
[(hibitors)-204.8(signicantly)-211.5(more)-202.6(potent)-203.9(than)-207.3(native)-205(C1-INH.)-208.6(Subtle)]TJ
T*
[(changes)-316.3(such)-304.9(as)-314.2(increased)-314(blood)-305.1(pressure)-315.9(or)-307.4(defective)-314.3(bri-)]TJ
T*
[(nolysis)-295.6(may)-299.4(be)-291.3(absent)-302.6(in)-290.3(the)-298.3(mouse)-295.7(and)-292.4(not)-297.2(observed)-298.9(in)-290.3(the)]TJ
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[(few)-350.9(prekallikre)-10.2(in-decient)-349.9(patients.)-354.6(Ecallantide,)-356(while)-353.4(well)]TJ
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[(tolerated,)-253.3(is)-249.8(used)-247.3(for)-250.9(treatment)-251.1(of)-249.8(HAE)-248.1(attacks.)-256.6(It)-244.2(has)-251.9(a)-249.9(short)]TJ
T*
[(half-life)-242.9(and)-234.9(does)-235.8(not)-239.6(cause)-233.4(long-l)-6.8(asting)-232.5(inhibition)-242.1(of)-232.6(plasma)]TJ
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[(kallikrein.)-351.3(The)-351.2(long-term)-346.6(safety)-348.7(of)-347.7(kallikrein)-347.9(inhibition,)-349.2(by)]TJ
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[(either)-308.7(an)-302.9(oral)-310.9(inhibitor)-304.1(or)-301.7(long-acting)-308.5(antibody,)-307.4(can)-305.1(only)-304(be)]TJ
T*
[(established)-269(by)-255.6(clinical)-266.2(trials.)]TJ
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[(Similar)-246.4(concerns)-248.2(apply)-248.7(to)-244.2(ongoing)-244(Factor)-245(XIIa)-248.3(inhibition.)]TJ
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[(Humans)-458.9(lacking)-453.8(Factor)-458.1(XII)-453.4(\(also)-455.8(called)-459.6(Hageman)-456.8(factor\))]TJ
T*
[(appear)-349.9(normal)-348.9(and)-344.3(have)-346.6(a)-347.8(phenotype)-346.4(similar)-344.3(to)-347.9(those)-346.4(lack-)]TJ
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[(ing)-441.2(kallikrein:)-447(increased)-446.4(aPTT)-445.5(but)-441.2(no)-439.9(increase)-445.3(in)-440.1(clinical)]TJ
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(bleeding.)Tj
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(27)Tj
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[(Recent)-414.4(data)-415.8(on)-411.1(Factor)-417.8(XIIdecient)-415(mice)-417(also)]TJ
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25.5097 69.0301 TD
[(frequency)-266.8(of)-267.1(bleeding.)]TJ
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(28)Tj
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[(While)-268.4(there)-267.1(have)-265.9(been)-265.9(a)-267.2(number)-268.2(of)]TJ
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[(Factor)-314.1(XIIdecient)-311.4(patients)-316.6(who)-309.4(suffered)-316.1(from)-310.8(thrombosis)]TJ
0 -1.1116 TD
[(clinically,)-312.3(recent)-234.8(data)-237.2(indicate)-243.1(protection)-238.3(from)-235.9(thrombosis)-236.7(in)]TJ
T*
[(patients)-276.3(with)-276.2(a)-278.7(deciency)-279.5(in)-278.8(Factor)-273.8(XII.)]TJ
7.3823 0 0 6.5614 469.4172 696.6423 Tm
(25)Tj
9.843 0 0 9.843 479.5652 692.277 Tm
[(Nonetheless,)-279(cau-)]TJ
-17.1409 -1.1116 TD
[(tion)-275.4(is)-278.6(warranted)-285(until)-276.6(the)-281.1(safety)-279.5(of)-278.6(Factor)-279.6(XIIa)-282.8(inhibition)-282.4(is)]TJ
0 -1.1174 TD
[(demonstrated,)-326.7(particularly)-328.2(in)-319.1(HAE)-328.8(patients)-322.4(for)-325.8(whom)-323.3(long-)]TJ
0 -1.1116 TD
[(term)-260.3(treatment)-262.7(would)-265.7(be)-256.8(required.)]TJ
/F4 1 Tf
9.9626 0 0 9.9626 310.8472 635.4707 Tm
(Summary)Tj
/F3 1 Tf
9.843 0 0 9.843 322.8094 617.6691 Tm
-.0201 Tc
[(The)-425.5(l)-4(ast)-424.5(6)-424.4(years)-424.2(h)1.8(a)-5.1(v)1.8(e)-425.5(s)2(e)-5.1(e).7(n)-424.4(d)1.8(ramatic)-425.5(i)-4(mprove)-5.1(ment)-424.5(in)-424.4(the)]TJ
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[(tr)-5.3(eat)-5.4(ment)-235.8(o)-5.3(p).4(ti)-5.5(ons)-235.5(a)-6.5(v).4(ai)-5.4(lab)-5.3(l).3(e)-236.9(f).5(o)-5.3(r)-229.9(p)-5.3(a)-.7(ti)-5.4(en)-5.3(ts)-235.5(wi)-5.5(th)-235.7(HAE)-236.9(in)-235.7(t)-5.5(h).5(e)-236.9(U)-.4(ni)-5.5(te)-6.5(d)]TJ
0 -1.1116 TD
-.0217 Tc
[(St)-5.6(ate)-6.7(s).4(,)-313.1(w)-.6(i)-5.7(t).1(h)-316.5(a)-.9(pp)-5.5(rov)-5.5(a)-.9(l)-310.9(o)-5.5(f)-310.8(t)-5.6(arg)-5.5(e)-.9(te)-6.7(d)-310.8(t)-5.7(her)-5.5(a)-.9(pi)-5.7(es)-316.3(for)-316.5(bot)-5.7(h)-310.8(p)-5.5(rev)-5.5(e)-.9(nt)-5.6(ion)]TJ
T*
[(and)-368.3(t)-5.5(rea)-6.6(t).2(me)-6.6(nt)-368.4(of)-368.2(a)-6.6(c)-.8(ut)-5.5(e)-369.4(a)-.8(tt)-5.6(ack)-5.4(s.)-370.6(Exp)-5.4(a)-.8(nd)-5.4(ing)-368.3(t)-5.5(he)-369.4(in)-5.4(dic)-6.6(a)-.8(ti)-5.6(on)-5.4(s)-368.1(f).4(or)]TJ
0 -1.1174 TD
[(the)-6.7(s).4(e)-455.9(t).1(he)-6.7(rap)-5.5(i).1(es)-454.6(to)-454.8(in)-5.5(clu)-5.5(d).2(e)-450.2(c)-6.7(hil)-5.6(d).2(re)-6.7(n)-449(o)-5.5(f)-449(a)-.9(l)-5.7(l)-449.1(a)-6.7(g).2(es)-454.6(sh)-5.5(oul)-5.6(d)-449(a)-.9(l)-5.7(l).1(ow)]TJ
0 -1.1116 TD
0 Tc
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T*
[(tinues)-370.7(to)-370.9(move)-375.4(rapidly)-372(forward.)-375.9(New)-374.8(approaches)-378.3(currently)]TJ
T*
-.0202 Tc
[(u)-20.2(n).6(d)-20.2(e)-.5(r)-412.9(a)-20.2(ct)-20.2(i)-5.4(v)-20.2(e)-403.7(i)-20.2(nv)-20.2(es)-20.2(t)-5.1(i)-20.2(ga)-20.2(ti)-20.2(on)-413(i)-20.2(n)-5.2(c)-20.2(l)-.7(u)-20.2(d).6(e)-414.1(i)-20.2(nh)-20.2(ib)-20.2(i)-5.3(t)-20.2(io)-20.2(n)-402.5(o)-20.2(f)-408.3(p)-20.2(la)-20.2(sm)-20.2(a)-404.9(k)-20.2(al)-20.2(-)]TJ
0 -1.1174 TD
0 Tc
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0 -1.1116 TD
[(ac)18.5(ti)20.6(ng)-630(in)20.7(hi)20.7(bi)20.7(to)20.7(ry)-630(an)19.7(ti)20.6(bo)20.8(dy)15.1(.)-637(A)0(l)19.8(t)0(e)19.6(r)0(n)20.9(a)0(t)19.5(i)0(v)15(e)-635.8(ap)19.7(pr)20.9(oa)13.9(ch)19.7(es)-625.2(mi)19.5(gh)20.8(t)]TJ
T*
[(in)20.7(cl)19.5(ud)20.8(e)-428.5(i)0(n)20.7(h)0(i)20.7(b)0(i)20.7(t)0(i)14.8(o)0(n)-411.1(o)0(f)-416.9(F)0(a)19.8(c)0(t)19.5(o)0(r)-416.9(X)0(I)20(I)0(a)19.7(,)-423.9(wh)20(ic)13.8(h)-421.6(i)0(s)-416.8(c)0(u)19.7(r)0(r)20.9(e)0(n)19.7(t)0(l)14.8(y)-421.6(be)19.7(in)20.7(g)]TJ
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[(pu)20.8(rs)21.1(ue)19.7(d)-248.8(a)0(s)-233.6(a)-249.9(th)20.7(er)19.7(ap)19.7(y)-248.8(f)0(o)20.9(r)-243(ot)14.9(he)19.7(r)-243(i)0(l)20.6(l)0(n)15(e)0(s)19.9(s)0(e)19.9(s)-248.6(ca)18.5(us)21(ed)-233.7(by)-238.3(th)20.7(ro)20.9(mb)19.6(os)15.3(is)20.9(.)]TJ
0 -1.1116 TD
[(Th)19.6(es)19.9(e)-365.1(n)0(o)20.8(v)0(e)19.7(l)-369.8(th)20.7(er)19.7(ap)19.7(ie)19.6(s)-369.5(s)0(h)21(o)0(u)20.8(l)0(d)-353.7(h)0(e)19.7(l)0(p)-359.4(m)0(o)19.6(v)0(e)-354.7(t)0(h)20.7(e)-365.1(e)19.8(ld)-359.4(cl)19.5(os)21(er)-354.7(to)20.7(-)]TJ
T*
[(wa)18.8(rd)-318.9(th)20.7(e)-330.6(u)0(l)20.7(t)0(i)20.6(m)0(a)18.4(t)0(e)-320.3(g)0(o)20.8(a)0(l)-320.3(o)0(f)-313.2(a)-330.6(th)20.7(er)19.7(ap)13.9(y)-323.6(t)0(h)20.7(a)0(t)-320.3(e)0(f)19.7(f)0(e)14(c)0(t)19.5(i)0(v)20.7(e)0(l)19.6(y)-329.4(pr)20.9(ev)19.7(en)19.7(ts)]TJ
0 -1.1174 TD
[(al)19.5(l)-323.8(H)0(A)19.1(E)-324.8(at)19.5(ta)19.5(ck)19.7(s)-323.4(w)0(i)19.8(t)0(h)-313.3(m)0(i)19.5(n)0(i)14.9(m)0(a)18.4(l)-323.8(in)20.7(co)19.7(nv)20.8(en)19.7(ie)19.5(nc)19.7(e)-324.8(t)0(o)-313.4(p)0(a)19.7(t)0(i)14.8(e)0(n)19.7(t)0(s)20.9(.)]TJ
/F4 1 Tf
9.9626 0 0 9.9626 310.8472 440.3337 Tm
[(Autho)-9.2(r)-332(Disc)-8.2(losure)-336.6(Sta)-8.2(tement)]TJ
/F3 1 Tf
9.843 0 0 9.843 322.8094 422.4755 Tm
[(The)-287.9(author)-290.1(has)-286.5(received)-295.8(research)-289.7(support)-289.8(from)-293.6(Dyax)-288.7(and)]TJ
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[(Shire,)-332.6(and)-332.8(has)-338.3(been)-335(a)-330.6(consultant)-341.8(for)-331.5(Dyax.)]TJ
/F4 1 Tf
9.9626 0 0 9.9626 310.8472 386.2487 Tm
[(Referen)-9.9(ces)]TJ
/F3 1 Tf
9.2951 0 0 9.2951 315.496 369.9778 Tm
[(1.)-500.4(Cicardi)-344.7(M,)-267.8(Aberer)-271.7(W,)-272.9(Banerji)-271.6(A,)-270.2(et)-266.2(al.)-272.4(Classication,)-274.4(diag-)]TJ
1.2503 -1.1284 TD
[(nosis,)-230.2(and)-230.3(approach)-229.6(to)-231.5(treatment)-233.7(for)-230.7(angioedema:)-236.4(consensus)]TJ
T*
[(report)-771.5(from)-767.2(the)-772.6(Hereditary)-775.4(Angioedema)-771(International)]TJ
0 -1.1223 TD
[(Working)-257.2(Group.)-260.9(Allergy)-264.1(2014;69:602616.)]TJ
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[(2.)-500.4(Zuraw)-547.4(BL.)-543.8(Clinical)-554.9(practice:)-549.4(hereditary)-548.2(angioedema.)-548(N)]TJ
1.2503 -1.1223 TD
[(Engl)-331.3(J)-334.7(Med)-333.3(2008;359:10271036.)]TJ
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[(3.)-500.4(MacGinnitie)-390.9(AJ.)-397.5(Pediatric)-389.5(hereditary)-395.7(angioedema.)-395.5(Pediatr)]TJ
1.2503 -1.1223 TD
[(Allergy)-331.2(Immunol)-337.4(2014;25:420427.)]TJ
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[(4.)-500.4(Bork)-471.2(K,)-465.3(Hardt)-471.8(J,)-469(Witzke)-476(G.)-471.4(Fatal)-468.3(laryngeal)-472.5(attacks)-475.1(and)]TJ
1.2503 -1.1223 TD
[(mortality)-462.5(in)-463.2(hereditary)-468.9(angioedema)-468.6(due)-462.1(to)-463.2(C1-INH)-470.9(de-)]TJ
0 -1.1284 TD
[(ciency.)-336.3(J)-334.7(Allergy)-331.2(Clin)-333.6(Immunol)-337.4(2012;130:692697.)]TJ
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[(5.)-500.4(Pappalardo)-329.8(E,)-331.5(Cicardi)-332.5(M,)-334.9(Duponchel)-334(C,)-328.3(et)-333.3(al.)-333.3(Frequent)-331.4(de)]TJ
1.2503 -1.1284 TD
[(novo)-305.5(mutations)-313.5(and)-303.5(exon)-309.7(deletions)-312.1(in)-310.8(the)-309(C1inhibitor)-305.3(gene)]TJ
0 -1.1223 TD
[(of)-246.6(patients)-250.9(with)-251.1(angioedema.)-255.2(J)-249.3(Allergy)-251.9(Clin)-254.3(Immunol)-245.9(2000;)]TJ
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(106:11471154.)Tj
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[(6.)-500.4(Davis)-486.9(AE)-485.6(III.)-483.2(C1)-486.9(inhibitor)-483.2(and)-486.5(hereditary)-487.2(angioneurotic)]TJ
1.2503 -1.1284 TD
[(edema.)-336.3(Ann)-331.4(Rev)-332.7(Immunol)-337.4(1988;6:595628.)]TJ
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[(7.)-500.4(Banerji)-253.3(A,)-258(Sloane)-255.6(DE,)-253.9(Sheffer)-257.1(AL.)-253.9(Hereditary)-257(angioedema:)]TJ
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[(a)-413(current)-416(state-of-the-art)-424(review,)-415.2(V:)-416(attenuated)-419.1(androgens)]TJ
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[(for)-425.9(the)-424.9(treatment)-434.9(of)-423.5(hereditary)-432.3(angioedema.)-426(Ann)-429(Allergy)]TJ
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[(Asthma)-334.1(Immunol)-331.3(2008;100:S1922.)]TJ
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(287:452454.)Tj
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1.2503 -1.1223 TD
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[(hered)-4.9(i)1.7(t)-4.4(a)-3(ry)-316(ang)-4.9(i)1.7(o)-4.9(e)-3(dema.)-315.9(A)-6.5(ll)-4.4(ergy)-316(As)-4.1(t)-4.4(h)1.2(m)-4.5(a)-314.1(Pro)-4.9(c)-314.1(2)-4.9(011)-4.9(;3)-4.9(2:)-4.4(17)-4.9(2)-4.9(1.)]TJ
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1.7505 -1.1223 TD
[(TJ)23.1(.)-347.7(F)0(r)18.9(e)0(s)20.8(h)-347.8(fr)19.5(oz)19.9(en)-339.9(pl)24.7(as)14.7(m)12.5(a)-352(fo)21.8(r)-350.1(t)12.6(he)-340(t)12.6(r)0(e)17.6(a)14(tm)19(en)19.9(t)-347.2(o)0(f)-344.2(h)0(e)26(r)0(e)17.6(d)0(i)18.6(t)12.6(ar)17.6(y)-347.8(a)14(n-)]TJ
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[(11.)-500.5(Zuraw)-364.5(BL,)-366.9(Busse)-373.9(PJ,)-362.2(White)-368(M,)-371.5(et)-363.8(al.)-369.9(Nanoltered)-367.5(C1)-371(in-)]TJ
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[(hibitor)-282.2(concentrate)-286.1(for)-279.5(treatment)-282.5(of)-283.2(hereditary)-279.8(angioedema.)]TJ
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[(N)-331.1(Engl)-337.4(J)-328.6(Med)-339.4(2010;363:513522.)]TJ
/F4 1 Tf
8.9663 0 0 8.9663 59.7543 749.7069 Tm
[(FUTURE)-340.1(HAE)-332.3(THERAPY)]TJ
53.0113 0 TD
(179)Tj
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[(nanoltered)-402.5(C1-inhibitor)-399.2(in)-396.2(hereditary)-401.8(angioedema.)-395.5(Am)-397.9(J)]TJ
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[(13.)-500.5(Yoo)-343.6(SM,)-338(Khan)-341.8(DA.)-345.1(Implantable)-343.7(venous)-339.7(access)-345.3(device)-342.3(as-)]TJ
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[(14.)-500.5(Babu)-503.6(YS,)-498.9(Wilson)-497.2(R,)-505.1(Zhang)-500.9(J,)-499.5(Cornpropts)-497.4(M,)-499.6(Collis)-503.2(P,)]TJ
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[(Sheridan)-386.3(W.)-388.8(A)-386(simple,)-386.9(sensitive)-390.5(assay)-391.6(to)-384(monitor)-386(plasma)]TJ
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[(plasma.)-336.8(J)-334.7(Allergy)-331.2(Clin)-339.7(Immunol)-331.3(2014;133:AB40.)]TJ
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[(15.)-500.5(Collis)-332.4(P,)-332.5(Cornpropst)-332.7(M,)-334.9(Collier)-333.9(J,)-328.7(Sheridan)-337.5(W.)-327.8(BCX4161,)]TJ
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[(an)-553.4(oral)-555.5(kallikrein)-558.8(inhibitor:)-555.9(safety)-559.1(and)-553.6(pharmacokinetic)]TJ
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[(results)-419.4(of)-417.4(a)-419.1(phase)-423(I)-417.2(study)-420.1(in)-420.6(health)-416.8(volunteers.)-425(J)-420.1(Allergy)]TJ
T*
[(Clin)-333.6(Immunol)-337.4(2014;133:AB39.)]TJ
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0 -1.1284 TD
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[(1)36.4(7)36.4(.)-464.1(ht)6.3(tp:)6.3(//cli)6.3(nicalt)6.3(r)-2.7(i)6.3(a)1.6(ls.g)5.8(ov)5.8(/ct2)5.8(/sho)5.8(w/)6.3(reco)5.8(rd)5.8(/NCT0)5.8(198)5.8(47)5.8(88)]TJ
1.7505 -1.1223 TD
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[(\(acce)-5.7(s)5.5(s)-.6(ed)-330.9(May)-337(1)4.6(6,)-330.8(2014\).)]TJ
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