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T*
[(ra)19.2(ti)16.5(ng)-246.2(th)18.9(e)-257.2(e)0(f)30.6(f)0(e)19.2(c)0(t)-249(o)0(f)-242.1(t)0(h)13.2(e)0(i)18.4(r)-252.7(tr)17.3(ea)14.7(t)13.9(m)0(e)12(n)0(t)-242.9(a)0(s)-247.8(")13.4(go)15.5(od)21.2(")-254.1(o)0(r)-247.8(")0(e)17.9(x)0(c)15.1(e)0(l)18.4(l)0(e)18.4(n)0(t)18.9(")]TJ
0 -1.0471 TD
[(on)-462.5(a)-467.8(f)0(i)17.3(v)0(e)15.1(-)0(p)19.6(o)0(i)18.9(n)0(t)-459.2(s)0(c)13.9(a)0(l)18.5(e)-467.8(ra)13.5(ng)21.2(in)18.9(g)-473.1(f)0(r)18(o)0(m)-459.9(")0(w)14.3(o)0(r)19.6(s)0(e)13.9(n)0(i)18.9(n)0(g)21.2(")-470.3(to)-464.8(")13.4(n)0(o)]TJ
0 -1.0527 TD
[(ch)15.1(an)20.8(ge)15.1(")13.4(,)-262.1("f)16.7(ai)18.4(r")16.7(,)-262.2(")0(g)18.3(o)0(o)15.5(d)0(")-249.2(a)0(n)15.1(d)-262.5(")13.4(e)0(x)15.1(c)0(e)14.7(l)13.9(le)12.8(nt)18.9(")-259.8(w)0(o)17.3(u)0(l)18.9(d)-262.5(be)-252.3(in)13.2(cl)18.4(ud)21.2(ed)]TJ
0 -1.0471 TD
[(in)-254.3(th)13.2(is)-255.5(ca)20.4(te)12.8(go)21.2(ry)76.5(.)-262.1(T)0(h)17.1(e)0(s)19.6(e)-268.6(en)20.8(d)-268.2(p)0(o)21.2(i)0(n)13.2(t)13.9(s)-269.4(o)0(f)-253.5(p)0(r)14(i)0(m)15.7(a)0(r)19.2(y)-262.5(in)13.2(te)18.4(re)19.2(st)-255.5(we)11.2(re)]TJ
0 -1.0527 TD
[(ex)15.1(tr)17.3(ac)20.4(te)18.4(d)-211.3(f)0(r)18(o)0(m)-203.8(r)0(e)19.2(l)0(e)18.4(v)0(a)15.1(n)0(t)-203.1(t)0(r)17.3(i)0(a)18.4(l)0(s)-198.6(o)0(n)15.5(l)0(y)-197.4(w)0(h)17.3(e)0(n)-201.1(t)0(h)13.2(e)0(y)-201.1(w)12.4(er)13.5(e)-206(r)0(e)13.5(p)0(o)21.2(r)0(t)17.3(e)0(d)]TJ
0 -1.0471 TD
[(in)-362.4(di)13.2(ch)20.8(ot)18.9(om)12.4(ou)21.2(s)-371.8(f)0(o)13.9(r)0(m)-364.8(\()]TJ
/F5 1 Tf
9.1276 0 TD
[(i.)19.2(e.)]TJ
/F4 1 Tf
1.5535 0 TD
[(nu)21.2(mb)12.4(er)-362(of)-367.3(pa)20.8(ti)16.5(en)20.8(ts)-369.3(w)12.4(i)0(t)16.5(h)-376.3(N)12.4(A)0(C)]TJ
-10.6812 -1.0528 TD
[(an)15.1(d)-245.5(p)0(l)18.9(a)0(c)20.4(e)0(b)15.1(o)-245.5(wi)14.9(th)-237.2(th)18.9(e)-245.9(e)0(n)15.1(d)-245.5(po)15.5(i)13.9(n)0(t)13.2(\))0(.)-236.1(T)0(h)17.1(e)0(r)19.2(e)-245.9(wa)16.9(s)-246.6(n)0(o)-240.5(i)0(n)18.9(t)0(e)18.4(n)0(t)18.9(i)0(o)13.2(n)-245.5(to)]TJ
0 -1.0471 TD
[(an)15.1(al)18.5(ys)20(e)-354(q)0(u)21.2(a)0(n)15.1(t)0(i)16.5(t)0(a)18.4(t)0(i)16.5(v)0(e)20.8(l)0(y)-345.3(f)0(o)19.6(r)0(c)13.5(e)0(d)-343.4(e)0(x)20.8(p)0(i)13.2(r)0(a)19.2(t)0(o)18.9(r)0(y)-344.6(v)0(o)15.5(l)13.9(um)12.4(e.)-343(D)12.4(a)0(t)12.8(a)-348.3(on)]TJ
0 -1.0528 TD
[(fo)19.6(rc)13.5(ed)-189.7(ex)20.8(pi)13.2(ra)19.2(to)18.9(ry)-190.9(vo)15.5(lu)18.9(me)-192.9(i)13.9(n)-199.9(on)15.5(e)-200.3(s)0(e)19.6(c)0(o)20.8(n)0(d)-189.3(\()0(F)14.7(E)0(V)]TJ
7.97 0 0 7.97 233.972 143.887 Tm
(1)Tj
9.963 0 0 9.963 237.883 143.887 Tm
[(\),)-190.5(pe)15.1(ak)-189.7(fl)17.3(ow)79.9(,)]TJ
-18.0277 -1.0471 TD
[(an)15.1(d)-456(v)0(i)18.9(s)0(c)19.6(o)0(s)14.4(i)0(t)16.5(y)-456(an)15.1(d)-456(v)0(o)21.2(l)0(u)13.2(m)0(e)-448.9(o)0(f)-447(m)0(u)12.4(c)0(u)20.8(s)-457.2(we)16.9(re)-453.1(no)21.2(t)-458.4(a)0(n)15.1(a)0(l)18.4(y)0(s)20(e)0(d)]TJ
0 -1.0528 TD
[(be)15.1(ca)20.4(us)14.4(e)-257.2(t)0(h)13.2(e)0(s)19.6(e)-262.9(en)20.8(d)-262.5(p)0(o)15.5(i)0(n)18.9(t)0(s)-249.8(w)0(e)16.9(r)0(e)-253.9(r)0(e)13.5(p)0(o)21.2(r)0(t)17.3(e)0(d)-252.3(i)0(n)13.2(c)0(o)20.8(n)0(s)14.4(i)0(s)17.7(t)0(e)18.4(n)0(t)18.9(l)0(y)81.4(,)-262.1(an)15.1(d)]TJ
0 -1.0471 TD
[(be)15.1(ca)20.4(us)14.4(e)-302.8(t)0(h)13.2(e)0(y)-297.8(w)0(e)16.9(r)0(e)-299.4(r)0(e)19.2(g)0(a)15.1(r)0(d)19.6(e)0(d)-297.8(a)0(s)-299(s)0(u)14.4(r)0(r)18(o)0(g)21.2(a)0(t)12.8(e)-308.5(en)20.8(d)-308.1(p)0(o)15.5(i)13.9(nt)13.2(s.)-298.2(D)12.4(a)0(t)12.8(a)]TJ
25.1977 66.1583 TD
[(on)-303.1(ad)20.8(ve)15.1(rs)18.4(e)-308.5(d)0(r)19.6(u)0(g)-303.1(r)0(e)19.2(a)0(c)14.7(t)13.9(io)13.2(ns)20(,)-307.7(w)0(h)17.3(e)0(n)-297.8(r)0(e)13.5(p)0(o)21.2(r)0(t)17.3(e)0(d)-303.5(i)13.9(n)-308.1(d)0(i)13.2(c)0(h)20.8(o)0(t)18.9(o)0(m)12.4(o)0(u)21.2(s)]TJ
0 -1.0471 TD
[(fo)13.9(rm)16.5(,)-324.7(w)12.4(er)13.5(e)-325.5(e)0(x)20.8(t)0(r)17.3(a)0(c)14.7(t)0(e)18.4(d)-325.1(an)20.8(d)-325.1(a)0(n)15.1(a)0(l)18.5(y)0(s)20(e)0(d)-314.9(q)0(u)15.5(a)0(n)20.8(t)0(i)16.5(t)0(a)18.4(t)0(i)16.5(v)0(e)15.1(l)0(y)81.4(.)]TJ
/F5 1 Tf
0 -3.1582 TD
[(Risk)-341.2(stratificat)-14.1(ion)]TJ
/F4 1 Tf
1.0015 -2.0998 TD
[(Th)17.1(er)13.5(e)-223.1(w)0(a)16.9(s)-229.6(an)-212.5(at)12.8(te)18.4(mp)18.1(t)-225.1(t)0(o)-220.2(e)0(s)19.6(t)0(i)16.5(m)0(a)17.7(t)0(e)-214.9(t)0(h)13.2(e)-223.1(ef)24.9(fi)17.3(ca)20.4(cy)-218.2(of)-219.4(N)12.4(A)0(C)-220.7(i)0(n)]TJ
-1.0015 -1.0471 TD
[(pa)15.1(ti)16.5(en)20.8(t)-282(p)0(o)15.5(p)0(u)21.2(l)0(a)18.4(t)0(i)16.5(o)0(n)15.5(s)-275.1(wi)14.9(th)-271.4(di)18.9(f)14.7(f)0(e)19.2(r)0(e)19.2(n)0(t)-271.4(u)0(n)15.5(d)0(e)20.8(r)0(l)17.3(y)0(i)13.2(n)0(g)-269(r)0(i)17.3(s)0(k)20(s)0(.)-269.8(I)0(t)-273(w)0(a)16.9(s)0(,)]TJ
0 -1.0527 TD
[(th)13.2(er)19.2(ef)19.2(or)13.9(e,)-200.7(in)18.9(te)18.4(nd)15.5(ed)-201.1(t)13.9(o)-211.3(cl)18.5(as)13.9(si)17.7(fy)-196.6(tr)17.3(ia)12.8(l)-208(p)0(o)21.2(p)0(u)15.5(l)0(a)18.4(t)0(i)16.5(o)0(n)15.5(s)-206.8(in)18.8(to)-203.1(th)18.9(os)20(e)-211.7(a)0(t)]TJ
0 -1.0471 TD
[("l)15.9(ow)17.3(",)-305.7("m)15.1(ed)20.8(iu)18.9(m")-309.2(an)20.8(d)-313.7(")0(h)12.6(i)13.9(gh)15.5(")-316.7(r)0(i)17.3(s)0(k)20(.)-313.4(Re)16.1(le)18.4(va)15.1(nt)-305.5(fa)19.2(ct)18.5(or)13.9(s)-309.3(c)0(o)15.1(n)0(s)20(i)0(-)]TJ
0 -1.0527 TD
[(de)15.1(re)19.2(d)-308.1(w)0(e)16.9(r)0(e)-293.7(n)0(u)15.5(m)0(b)18.1(e)0(r)-299.4(o)0(f)-293.3(e)0(x)15.1(a)0(c)20.4(e)0(r)13.5(b)0(a)20.8(t)0(i)16.5(o)0(n)15.5(s)-303.6(in)-294.1(th)13.2(e)-302.8(p)0(r)19.6(e)0(v)15.1(i)0(o)18.9(u)0(s)-298.6(y)0(e)20.8(a)0(r)47.7(,)]TJ
0 -1.0471 TD
[(nu)15.5(mb)18.1(er)-521.4(of)-521(pr)14(ev)20.8(io)18.9(us)-520.6(ho)15.5(sp)20(it)16.5(al)18.5(iz)12.8(at)18.5(io)18.9(ns)-520.6(an)15.1(d)-530(l)13.9(un)15.5(g)-530(f)0(u)19.6(n)0(c)15.1(t)0(i)16.5(o)0(n)]TJ
0 -1.0527 TD
[(be)15.1(fo)19.6(re)-316.5(th)18.8(e)-325.5(s)0(t)17.7(a)0(r)13.5(t)-321.8(of)-316.1(th)18.9(e)-325.5(t)0(r)17.3(i)0(a)18.4(l)0(.)]TJ
/F5 1 Tf
0 -3.1526 TD
[(Dat)-8.6(a)-330.8(analys)-8.6(is)]TJ
/F4 1 Tf
1.0015 -2.0998 TD
[(Re)16.1(la)12.8(ti)22.2(ve)-212.5(be)15.1(ne)20.8(fi)17.3(t)-225.1(o)0(r)-208(r)0(e)13.5(l)13.9(at)12.8(iv)18.9(e)-217.4(r)0(i)17.3(s)0(k)-213.3(w)0(a)16.9(s)-218.2(ca)14.7(lc)18.4(ul)18.8(at)12.8(ed)-206.8(wi)14.9(th)-214.5(95)21.2(%)]TJ
-1.0015 -1.0471 TD
[(co)15.1(nf)19.6(id)13.2(en)20.8(ce)-360.8(in)18.8(te)12.8(rv)19.6(al)-362.8(\(C)14.9(I\))-357.5([1)13.9(4].)-373.4(A)-380.3(fixed)-383.8(effect)-375.6(model)-385.3([15])]TJ
0 -1.0528 TD
[(was)-360.6(used)-357.5(when)-360.2(data)-359.1(wer)-8.2(e)-354(combi)-9.7(ned.)-355.9(A)-357.5(statistical)-14.9(ly)-356.7(sig-)]TJ
0 -1.0471 TD
[(nifi)-9.4(cant)-370.4(dif)10.8(ference)-374.3(betw)-9.8(een)-367.3(NAC)-367.7(and)-366.9(con)-8.4(trol)-367.9(was)-366.3(assu-)]TJ
0 -1.0528 TD
[(med)-330.2(when)-331.7(the)-329.4(95)-7.2(%)-327.5(C)0(I)-326.5(o)0(f)-327.5(the)-329.4(relat)-11(ive)-329.4(benefit)-331.2(or)-333.2(risk)-326.9(did)]TJ
0 -1.0471 TD
[(not)-238(include)-238.5(1.)-228.8(As)-234.3(an)-229.6(e)-6.9(stimate)-239.6(of)-230.8(the)-232.7(clin)-8.2(ical)-236.2(relevance)-240.5(of)-230.8(a)]TJ
0 -1.0528 TD
[(treat)-11(ment)-578(effect,)-569.4(the)-579.8(numbe)-7.4(r-)12.3(n)-6.5(eeded-to-t)-11.1(reat)-576.9([16])-581(was)]TJ
0 -1.0471 TD
[(calcul)-10.6(ated)-376.1(for)-381.1(both)-375.3(indi)-7.8(vidual)-379.6(trials)-379.1(and)-378.3(combin)-10.5(ed)-371.8(data.)]TJ
0 -1.0528 TD
[(Fo)-6.4(r)-372.2(estimat)-11.9(ion)-374.6(of)-378.7(the)-375(freque)-8.6(ncy)-378.3(of)-373(drug-r)-9.4(elated)-380.4(advers)-8.2(e)]TJ
T*
[(effects,)-286.8(the)-283.9(numbe)-7.4(r)-281.2(needed)-290.3(to)-288.4(harm)-287(was)-286.7(calculated)-295.6(as)-282(for)]TJ
0 -1.0471 TD
[(numbe)-7.4(r-needed-to-treat)-502.4([17].)-496(Combi)-8.4(ned)-492.1(numbers-ne)-10.3(ed-)]TJ
0 -1.0527 TD
[(ed-to)-8.2(-trea)-10.2(t/harm)-225(were)-219.9(calcul)-10.6(ated)-222.5(using)-217.9(the)-221.3(weighte)-9.1(d)-217(mean)]TJ
0 -1.0471 TD
[(of)-236.4(the)-232.7(contr)-8.2(ol)-231.5(event)-240.3(rate)-235.5(\()]TJ
/F5 1 Tf
9.9471 0 TD
(i.e.)Tj
/F4 1 Tf
1.4397 0 TD
[(the)-232.7(inci)-8.2(dence)-238.3(of)-230.7(an)-235.2(end)-236(point)]TJ
-11.3868 -1.0527 TD
[(wi)-7.8(th)-430.7(placeb)-8.2(o\))-429.9(and)-435.2(the)-431.9(experi)-9.4(mental)-440.1(event)-433.8(rate)-434.6(\()]TJ
/F5 1 Tf
19.9511 0 TD
(i.e.)Tj
/F4 1 Tf
1.6389 0 TD
(the)Tj
-21.5899 -1.0471 TD
[(inci)-8.2(dence)-352.2(of)-350.2(the)-352.2(same)-355.3(end)-355.5(point)-350(wi)-7.8(th)-351(NAC\).)-353.3(A)-351.8(positive)]TJ
0 -1.0528 TD
[(numbe)-7.4(r-needed-to-treat)-718.7(indi)-7.8(cated)-707.3(how)-711.9(many)-712.2(patients)]TJ
0 -1.0471 TD
[(had)-241.7(to)-242.9(be)-240.9(exposed)-246.3(to)-242.9(NAC)-242.5(in)-242.9(order)-246.4(to)-237.2(achiev)-8.2(e)-240.2(a)-240.2(particu)-12.5(lar)]TJ
0 -1.0527 TD
[(outcom)-10.5(e)-336.9(\()]TJ
/F5 1 Tf
4.0858 0 TD
(e.g.)Tj
/F4 1 Tf
1.7754 0 TD
[(prevention)-344.8(of)-338.9(any)-332.8(e)-6.9(xacerbation)-10.7(\))-338.1(i)0(n)-334(one)-338.4(of)]TJ
-5.8613 -1.0471 TD
[(them)-9(,)-415.8(who)-421.6(would)-425.5(not)-420.1(have)-419.3(had)-418.1(this)-424.4(outcom)-10.5(e)-416.6(had)-418.1(they)]TJ
0 -1.0528 TD
[(all)-348.9(recei)-9(ved)-344.1(placeb)-8.2(o.)-348.3(A)-340.4(n)-6.5(egative)-347.1(numbe)-7.4(r-needed-to-treat)]TJ
0 -1.0471 TD
[(point)-230.5(esti)-9.4(mate)-231.3(indicated)-237.2(that)-230.1(the)-227(end)-230.3(point)-230.5(happened)-229.3(more)]TJ
0 -1.0527 TD
[(often)-503.3(wi)-7.8(th)-499(placebo.)-504.4(The)-496.2(95%)-505.4(CI)-497.2(around)-501.7(the)-500.2(numbe)-7.4(r-)]TJ
0 -1.0471 TD
[(nee)-8.8(ded-to-tr)-11.1(eat)-290(was)-286.7(obtai)-9(ned)-287.2(by)-286.1(taki)-8.2(ng)-286.1(the)-289.6(reciprocal)-11.5(s)-286.5(o)0(f)]TJ
0 -1.0527 TD
[(the)-232.7(values)-230.9(defin)-8.2(ing)-226.6(the)-232.7(95%)-226.6(CI)-229.8(for)-233.1(absolute)-234.8(risk)-230.2(reduction)]TJ
0 -1.0471 TD
[([18].)-359.4(A)-357.5(95%)-363.2(CI)-355(rangi)-8.2(ng)-354.3(from)-362.2(one)-355.5(limit)-363.6(with)-358.9(a)-354(n)-6.5(egative)]TJ
0 -1.0527 TD
[(value)-337.1(to)-334(anothe)-7.8(r)-326.7(w)0(i)-7.8(t)0(h)-328.3(a)-331.2(positive)-339.2(value)-337.1(indicated)-339.6(absence)]TJ
0 -1.0471 TD
[(of)-293.3(a)-291.4(stat)-9.4(istically)-299.6(signifi)-9.6(cant)-296.5(dif)10.8(ference)-300.4(between)-297.4(NA)-9.4(C)-290(and)]TJ
0 -1.0528 TD
[(placeb)-8.2(o)-313.7(\()]TJ
/F5 1 Tf
3.7273 0 TD
(i.e.)Tj
/F4 1 Tf
1.5251 0 TD
[(the)-312.4(CI)-320.8(included)-319(infinit)-10.8(y\).)-316.5(Calculatio)-11.7(ns)-315.7(were)]TJ
-5.2524 -1.0471 TD
[(perfor)-9.8(med)-273.3(using)-280.5(Excel)-272.9(versi)-9.4(on)-274.7(98)-269(on)-274.7(a)-268.6(P)0(o)-6.4(wer)-275.7(Macintosh)]TJ
0 -1.0528 TD
(G3.)Tj
/F7 1 Tf
9.8617 -3.1526 TD
[(Res)-7.8(ults)]TJ
/F5 1 Tf
-9.8617 -2.0998 TD
[(Retri)-8.6(eved)-340(trials)]TJ
/F4 1 Tf
1.0015 -2.0998 TD
[(Th)17.1(ir)17.3(ty)13.2(-n)19.6(in)18.9(e)-439.3(p)0(o)15.5(t)13.9(en)15.1(ti)16.5(al)18.5(ly)-430.7(re)19.2(le)18.4(va)15.1(nt)-430.7(tr)17.3(ia)18.5(ls)-426.2(on)-428.3(th)13.2(e)-433.7(e)0(f)24.9(f)0(e)19.2(c)0(t)-431.1(o)0(f)]TJ
-1.0015 -1.0527 TD
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[([Ref.])-8480.4(Patients)-337.5(n)-22540.7(Patient)-330.5(characteristics)-17753.2(Active)-333.4(drug*)-2533.9(Score)]TJ
3.3701 -2.1119 TD
(Entering)Tj
0.9168 -1.0559 TD
(trial)Tj
2.8074 1.0559 TD
[(Rand.)-1453.3(T)66.5(otal)]TJ
3.0793 -1.0559 TD
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14.0242 -1.0559 TD
[(at)-329.9(baseline)]TJ
10.4644 1.0559 TD
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-52.986 -2.1119 TD
([40])Tj
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[(34)-2193.1(34)-2642(29)-2926.5(15)-3476.6(14)-1124.5(Chronic)-333.1(bronchitis)-339.1(in)-336.5(all)]TJ
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[(;)-337(2)0(1)-334.1(\(72%\))]TJ
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T*
[(exacerbation)-333.6(rate)-336(not)-336(reported)]TJ
16.4838 2.1118 TD
(FEV)Tj
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[(20\26170%)-332.5(pred)-2230.7(Corticosteroid)-338.6(\(route)-336.2(NA\))-1504.6(NAC)-332.3(200)-333.6(mg)]TJ
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[(285)-1693(259)-2142(203)-2926(98)-2977.1(105)-1124(Chronic)-333.1(bronchitis)-339.1(in)-336.5(all)]TJ
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[(;)-337(203)]TJ
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[(\(100%\))-334.4(of)-335.1(analysed)-333.9(patients)-332.6(smokers/)]TJ
T*
(exsmokers;)Tj
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($)Tj
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[(1)-334.6(exacerbation)]TJ
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11.6025 1.0559 TD
[(NAC)-332.3(200)-333.6(mg)]TJ
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[(21)-2193.1(21)-2642(19)-2926.5(10)-3976.1(9)-1125(Chronic)-333.1(bronchitis)-339.1(in)-336.5(all)]TJ
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[(exacerbation)-333.6(rate)-336(not)-336(reported)]TJ
16.4838 1.0559 TD
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T*
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[(20)-334.1(weeks)]TJ
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T*
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T*
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18.1973 -1.0559 TD
[(of)-335.1(analysed)-333.9(patients)-332.6(smokers/)]TJ
T*
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T*
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[(252)-1693(252)-2142(181)-2926(90)-3476.6(91)-1124.5(Chronic)-333.1(bronchitis)-339.1(in)-336.5(all;)-333.7(223)-333.6(\(88%\))]TJ
18.1973 -1.0559 TD
[(of)-335.1(patients)-332.6(who)-336.9(entered)-334.2(the)-335.8(trial)]TJ
T*
(smokers/exsmokers;)Tj
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($)Tj
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(1)Tj
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(.)Tj
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(-1)Tj
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0.3351 -1.0559 TD
(L)Tj
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(-1)Tj
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(,)Tj
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[(P)-333.2(306\213136)-334.8(L)]TJ
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(.)Tj
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(-1)Tj
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(Bronchospasmolytics,)Tj
0.3351 -1.0559 TD
(corticosteroids,)Tj
T*
[(antialler)7.4(gics)]TJ
11.6025 2.1119 TD
[(NAC)-332.3(300)-333.6(mg)]TJ
/F5 1 Tf
5.874 0 TD
[(b.i.d.)-332(p.o.)]TJ
/F4 1 Tf
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[(24)-334.1(weeks)]TJ
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[(744)-1693(744)-2142(495)-2426.5(254)-2976.6(241)-1124(Chronic)-333.1(bronchitis)-339.1(in)-336.5(all)]TJ
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(+)Tj
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[(;)-337(121)]TJ
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T*
[(noxious)-335.1(work)-331(environment,)-339.6(328)-327.3(\(66%\))]TJ
T*
[(smokers/exsmokers;)-340.4(exacerbation)-333.6(rate)]TJ
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[(0,)-331.2(1\2613,)-330.2(4\2616)-333.6(exacerbations)]TJ
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(-1)Tj
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(FEV)Tj
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(1)Tj
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(>)Tj
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7.4294 -1.0559 TD
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T*
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[(NAC)-332.3(200)-333.6(mg)]TJ
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[(24)-334.1(weeks)]TJ
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[(526)-1693(526)-2142(526)-2426.5(258)-2976.6(268)-1124(All)-335.3(chronic)-334.4(bronchitis)]TJ
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[(;)-330.7(451)-333.6(\(86%\))]TJ
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T*
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(-1)Tj
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[(\(mean)-335(3\))]TJ
16.4838 3.1678 TD
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T*
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[(24)-334.1(weeks)]TJ
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0 -1.0528 TD
[([40].)-257(The)-257.2(event)-257.4(rate)-258.2(scatte)-11.7(r)-252.7(sugges)-7.4(ted)-255.5(superiori)-10.7(ty)-254.3(of)-253.5(NAC)]TJ
T*
[(\(fig.)-361.8(3\).)-356.3(Fo)-6.4(r)-355.2(each)-357.1(tri)-8.6(al,)-357.5(the)-357.9(event)-359.8(rate)-360.7(\()]TJ
/F5 1 Tf
15.7628 0 TD
(i.e.)Tj
/F4 1 Tf
1.5649 0 TD
[(p)-6.5(ercentage)-365.7(of)]TJ
-17.3277 -1.0471 TD
[(patien)-10.1(ts)-420.5(reporting)-430.6(improvem)-11.1(ent\))-428.5(was)-423.2(higher)-424.4(wi)-7.8(th)-419.3(NAC)]TJ
0 -1.0528 TD
[(than)-523.7(with)-529.6(placebo.)-527.2(The)-524.7(dif)10.8(ference)-533.7(in)-521.8(favour)-526(of)-521(NAC)]TJ
0 -1.0471 TD
[(reached)-236.2(statistical)-242.5(significan)-12.7(ce)-224.3(in)-231.5(the)-227(largest)-229.9(trial)-229.2(wi)-7.8(th)-225.8(61)26.9(1)]TJ
0 -1.0527 TD
[(patien)-10.1(ts)-340.8(\(66%)-342.8(of)-344.6(the)-340.8(pati)-8.2(ents)-342.8(of)-344.6(all)-343.2(trials\))-347.3(\(table)-347.5(2\))-344.6([55].)]TJ
0 -1.0471 TD
[(When)-431.4(the)-437.6(data)-433(from)-430.5(all)-434.2(five)-434.2(trials)-436(wer)-8.2(e)-428(combin)-10.5(ed,)-429.1(the)]TJ
0 -1.0527 TD
[(difference)-477.3(between)-479.5(NAC)-481.5(and)-475(placeb)-8.2(o)-473.1(was)-474.4(statistical)-14.9(ly)]TJ
0 -1.0471 TD
[(signifi)-9.6(cant.)-359.4(W)26.5(ith)-359.9(NAC,)-362.4(286)-355.1(of)-361.6(466)-355.1(\(61.4%)-8.2(\))-355.2(pati)-8.2(ents)-359.8(re-)]TJ
0 -1.0527 TD
[(porte)-8.2(d)-285.3(improvem)-11.1(ent,)-284.3(co)-7.6(mpared)-289(with)-290.6(160)-286.8(of)-287.7(462)-286.8(\(34.6%)-8.2(\))]TJ
0 -1.0471 TD
[(recei)-9(ving)-449.3(placeb)-8.2(o.)-445(The)-445(relat)-11(ive)-448.9(benefit)-450.7(wi)-7.8(th)-447.8(NAC)-447.3(was)]TJ
0 -1.0528 TD
[(1.78)-270.1(\(95%)-274.5(CI)-275.3(1.54\2612.05)-6.1(\);)-273(the)-272.5(numbe)-7.4(r-needed-to-treat)-280.5(for)]TJ
0 -1.0471 TD
[(one)-475(patient)-479.9(reporting)-481.8(improvem)-11.1(ent)-471.7(of)-475.4(their)-477.2(bronchi)-9.7(tis-)]TJ
0 -1.0528 TD
[(related)-337.3(symp)-7.4(tom)-7.8(s)-326.3(c)0(o)-7.6(mpared)-334.5(wi)-7.8(th)-328.3(placeb)-8.2(o)-330.8(was)-337.9(3.7)-332(\(95%)]TJ
0 -1.0471 TD
[(CI)-275.3(3.0\2614.9\))-6.9(.)-267.8(Exc)-6.8(lusion)-272.3(of)-276.3(the)-272.5(trial)-274.7(with)-273.5(the)-278.2(shortest)-277(study)]TJ
0 -1.0527 TD
[(perio)-8.2(d)-313.7([40])-319.2(had)-321.4(no)-314.5(impac)-10.2(t)-316.1(o)0(n)-314.5(this)-322(result)-319.8(\(rela)-10.2(tive)-315.5(benefi)-9.4(t)]TJ
0 -1.0471 TD
[(in)-459.2(favour)-463.4(of)-464.1(NAC)-458.7(1.7)-7.6(6)-456(\(95%)-462.3(CI)-463.1(1.53\2612.04)-6.1(\);)-460.7(numbe)-7.4(r-)]TJ
0 -1.0527 TD
[(needed-)-8.1(to-treat)-341.6(3.8)-337.7(\(95%)-337.1(CI)-337.9(3.0\2614.9\))-6.9(.)]TJ
/F5 1 Tf
0 -3.1924 TD
[(Sensi)-7.8(tivity)-339.3(analys)-8.6(is:)-337.5(impact)-338(of)-334(tri)-8.2(al)-334(size)]TJ
/F4 1 Tf
1.0015 -2.0998 TD
[(Th)17.1(e)-285.7(e)0(n)15.1(d)-285.3(po)15.5(in)18.9(t)-287.7(")0(n)18.3(o)-291(ex)20.8(ac)14.7(er)19.2(ba)15.1(ti)22.2(on)15.5(")-288.2(w)0(a)16.9(s)-286.5(ch)15.1(os)20(en)-280.8(to)-277.1(te)18.4(st)-278.2(th)13.2(e)]TJ
-1.0015 -1.0527 TD
[(im)15.7(pa)20.8(ct)-510.8(of)-509.6(t)13.9(r)0(i)11.6(a)0(l)-505.1(s)0(i)17.7(z)0(e)-508.8(o)0(n)-508(o)0(u)21.2(t)0(c)18.4(o)0(m)12.4(e)0(.)-502.3(F)0(o)16.3(r)-520.2(ea)20.4(ch)-508.4(tr)17.3(ia)18.4(l)-515.3(w)0(h)17.3(i)0(c)12.8(h)]TJ
0 -1.0471 TD
[(re)19.2(po)15.5(rt)17.3(ed)-309.2(th)18.9(e)-319.8(n)0(u)15.5(m)0(b)18.1(e)0(r)-310.8(o)0(f)-310.4(p)0(a)20.8(t)0(i)16.5(e)0(n)15.1(t)0(s)-306.7(w)0(i)14.9(t)0(h)18.9(o)0(u)15.5(t)-316.1(an)15.1(y)-313.7(e)0(x)15.1(a)0(c)14.7(e)0(r)19.2(b)0(a)20.8(t)0(i)16.5(o)0(n)]TJ
0 -1.0528 TD
[(\(t)17.3(ab)15.1(le)-305.9(2\),)-310.8(the)-329.4(size)-326.1(of)-327.5(the)-323.7(NAC)-333.5(group)-324.1(was)-326.5(plot)-7.8(ted)-323.7(agains)-9(t)]TJ
0 -1.0471 TD
[(contr)-8.2(ol)-254.3(event)-263.1(rate)-258.2(\()]TJ
/F5 1 Tf
7.5172 0 TD
(i.e.)Tj
/F4 1 Tf
1.4625 0 TD
[(the)-261.2(incidence)-263.6(of)-253.5(the)-261.2(end)-258.8(point)-259(with)]TJ
-8.9797 -1.0528 TD
[(placeb)-8.2(o\),)-606.7(relative)-613.6(benefi)-9.4(t)-606.3(and)-605.9(numbe)-7.4(r-needed-to-treat,)]TJ
0 -1.0471 TD
[(respec)-8.6(tively)-234.1(\(fig.)-230.9(4\).)-231.1(In)-225.1(eight)-230.9(of)-230.7(the)-227(nine)-233.5(trials,)-237.2(group)-227.3(sizes)]TJ
0 -1.0528 TD
[(ranged)-371.2(10\26198)-368(pati)-8.2(ents.)-371.6(In)-367.3(the)-363.6(nint)-7.8(h)-365(trial,)-371.8(the)-369.3(group)-369.6(size)]TJ
0 -1.0471 TD
[(was)-383.4(254)-377.9(pati)-8.2(ents)-382.6([55].)-382.2(Control)-386.3(event)-382.6(rates)-385.4(ranged)-382.6(~1)23.8(1\261)]TJ
25.1977 38.8949 TD
[(60%)-351.8([50,)-345.7(53],)-345.7(relative)-351.8(benefi)-9.4(t)-338.9(point)-350(estimat)-11.9(es)-344.6(1.10\2612.09)]TJ
0 -1.0527 TD
[([48,)-476.6(54])-476.2(and)-469.3(n)-6.5(umbers-nee)-10.7(ded-t)-8.2(o-treat)-480.7(3.5\26127)-470.8([54,)-476.6(55].)]TJ
0 -1.0471 TD
[(The)-280(lar)10.4(gest)-280.2(trial)-274.7([55])-279.4(had)-275.8(a)-274.3(control)-279.6(event)-274.5(rate)-281(of)-276.3(24%,)-272.5(the)]TJ
0 -1.0528 TD
[(highes)-8.6(t)-464.1(relative)-477(benefit)-467.7(\(2.19\))-468.3(a)-6.9(n)0(d)-462.5(the)-466(lowest)-470.1(numbe)-7.4(r-)]TJ
0 -1.0471 TD
[(nee)-8.8(ded-to-tr)-11.1(eat)-574.5(\(3.5\).)-581.7(The)-6.8(re)-578.3(was)-576.9(no)-576.3(eviden)-7.8(ce)-577.1(of)-577.9(any)]TJ
0 -1.0527 TD
[(relat)-11(ionship)-409.6(betw)-9.8(een)-407.1(group)-409.4(size)-411.5(and)-406.7(contr)-8.2(ol)-402.3(ev)-7.6(ent)-403.4(rate,)]TJ
0 -1.0471 TD
[(relat)-11(ive)-335.1(benefi)-9.4(t)-333.2(o)0(r)-333.2(numbe)-7.4(r-needed-to-treat,)-343.5(respec)-8.6(tive)-8.2(ly)64.4(.)]TJ
/F5 1 Tf
0 -3.0615 TD
[(Adv)-6.8(erse)-336.3(effe)-8.6(cts)]TJ
/F4 1 Tf
1.0015 -1.8494 TD
[(Si)14(x)-438.9(t)0(r)17.3(i)0(a)12.8(l)0(s)-431.9(w)0(i)14.9(t)0(h)-430.7(1)0(,)15.9(3)0(3)21.2(6)-444.6(tr)17.3(ea)20.4(te)12.8(d)-438.9(p)0(a)15.1(t)0(i)16.5(e)0(n)20.8(t)0(s)-431.9(r)0(e)13.5(p)0(o)21.2(r)0(t)17.3(e)0(d)-434.4(g)0(a)15.1(s)0(t)17.7(r)0(o)19.6(-)]TJ
-1.0015 -1.0471 TD
[(in)13.2(te)18.4(st)17.7(in)18.9(al)-544.9(ad)20.8(ve)15.1(rs)18.4(e)-553.2(r)0(e)13.5(a)0(c)20.4(t)0(i)16.5(o)0(n)15.5(s)-548.3([4)13.9(0,)-541.7(48)21.2(\2615)15.5(0,)-541.8(55)15.5(,)-552.4(5)0(7)21.2(])0(.)-543.3(W)37.9(it)16.5(h)]TJ
0 -1.0528 TD
[(NA)13.4(C,)-222.1(68)-223.5(of)-225.1(66)21.2(5)-234.1(\()0(1)19.6(0)0(.)15.9(2)0(%)18.9(\))-235.7(pa)20.8(ti)16.5(en)15.1(ts)-221.3(ha)15.1(d)-228.4(d)0(y)15.5(s)0(p)20(e)0(p)15.1(s)0(i)17.7(a)0(,)-223.5(d)0(i)18.9(a)0(r)19.2(r)0(h)19.6(o)0(e)15.1(a)]TJ
0 -1.0471 TD
[(or)-247.8(he)15.1(ar)19.2(tb)13.2(ur)19.6(n)-256.8(d)0(u)21.2(r)0(i)17.3(n)0(g)-246.2(t)0(h)13.2(e)-257.2(st)17.7(ud)21.2(y)-256.8(p)0(e)15.1(r)0(i)17.3(o)0(d)21.2(,)-256.5(co)15.1(mp)18.1(ar)19.2(ed)-246.6(wi)14.9(th)-248.6(73)-246.2(of)]TJ
0 -1.0528 TD
[(67)15.5(1)-393.4(\()0(1)19.6(0)0(.)15.9(9)0(%)18.9(\))-395(co)20.8(nt)18.9(ro)13.9(l)-390.1(p)0(a)15.1(t)0(i)22.2(e)0(n)15.1(t)0(s)-380.7(\()0(t)17.3(a)0(b)15.1(l)0(e)-385.6(3\).)-390.5(The)-405.2(relative)-414.4(risk)]TJ
0 -1.0471 TD
[(wi)-7.8(th)-413.6(NAC)-424.6(was)-417.5(0.96)-423.8(\(95%)-416.7(CI)-423.2(0.70\2611.30)-6.1(\);)-420.9(the)-414.8(numbe)-7.4(r-)]TJ
0 -1.0528 TD
[(nee)-8.8(ded-to-harm)-355.3(for)-346.9(one)-344.1(patient)-349(having)-348.8(a)-342.6(gastr)-9.4(ointestinal)]TJ
ET
1 i 
58.28 768.302 478.205 -0.51 re
f
188.277 743.867 69.165 -0.284 re
f
268.724 743.867 113.386 -0.284 re
f
58.28 713.99 478.205 -0.51 re
f
58.28 536.655 478.205 -0.51 re
f
BT
/F3 1 Tf
8.966 0 0 8.966 58.28 772.667 Tm
[(Table)-331.9(2.)-336.7(\261)]TJ
/F13 1 Tf
4.875 0 TD
0 Tw
(N)Tj
/F3 1 Tf
0.7208 0 TD
(-acetylcysteine)Tj
/F13 1 Tf
6.9236 0 TD
(versus)Tj
/F3 1 Tf
3.2689 0 TD
[(placebo)-334.6(in)-330.2(chronic)-333.7(bronchitis.)-335.8(Efficacy)-333.5(data)]TJ
/F4 1 Tf
-15.7883 -1.7135 TD
[([Ref.])-13210(Event)-331.9(rates)-336.7(%)-2921.2(Patients)-337.5(with)-334.8(end)-333.4(point/total)]TJ
27.8461 -1.0496 TD
[(patients)-332.6(n)]TJ
10.0345 1.0496 TD
[(Relative)-335.9(benefit)]TJ
-0.0126 -4.2174 TD
[(Mean)-333.3(\(95%)-334.5(CI\))]TJ
8.4537 4.2174 TD
[(Number)9.8(-needed-)]TJ
1.9285 -1.0496 TD
(to-treat)Tj
-1.7704 -3.1678 TD
[(Mean)-333.3(\(95%)-334.5(CI\))]TJ
-31.5893 1.0559 TD
[(W)32.8(ith)]TJ
-0.0759 -1.0559 TD
(NAC)Tj
4.5651 1.0559 TD
[(W)32.8(ith)]TJ
-0.5691 -1.0559 TD
(placebo)Tj
6.5379 1.0559 TD
[(W)32.8(ith)]TJ
-0.0822 -1.0559 TD
(NAC)Tj
7.0311 1.0559 TD
[(W)26.5(ith)]TJ
-0.5627 -1.0559 TD
(placebo)Tj
-31.7347 -2.0043 TD
[(Prevention)-333.9(of)-335.1(any)-333.4(exacerbation)]TJ
0 -1.0559 TD
[([48])-13347.6(39.8)-2739.2(19.0)-3953.2(39/98)-4685.1(20/105)-2787.7(2.09)-336.5(\(1.31\2613.32\))-2469.1(4.8)-330.7(\(3\26112\))]TJ
0 -1.0496 TD
[([49])-13347.6(70.0)-2739.2(44.4)-4452.7(7/10)-5185.1(4/9)-3788.3(1.58)-336.5(\(0.68\2613.63\))-2469.1(3.9)-330.7(\(1.5\261-5.7\))]TJ
0 -1.0559 TD
[([50])-13347.6(15.3)-2739.2(10.5)-3984.8(1)32.1(1/72)-5185.1(8/76)-3288.3(1.45)-336.5(\(0.62\2613.40\))-2715.7(21)-334.1(\(6.4\261-17\))]TJ
T*
[([51])-13347.6(51.4)-2739.2(32.4)-3953.2(18/35)-4716.7(1)32.1(1/34)-3288.3(1.59)-336.5(\(0.89\2612.85\))-2469.1(5.2)-330.7(\(2.4\261-27\))]TJ
T*
[([52])-13347.6(61.0)-2739.2(48.6)-3953.2(36/59)-4685.1(34/70)-3287.8(1.26)-336.5(\(0.92\2611.72\))-2469.1(8.0)-330.7(\(3.4\261-22\))]TJ
T*
[([53])-13347.6(67.2)-2739.2(60.0)-3953.2(41/61)-4685.1(36/60)-3287.8(1.12)-336.5(\(0.85\2611.47\))-2715.7(14)-334.1(\(4.1\261-10\))]TJ
T*
[([54])-13347.6(41.1)-2739.2(37.4)-3953.2(37/90)-4685.1(34/91)-3287.8(1.10)-336.5(\(0.77\2611.58\))-2715.7(27)-334.1(\(5.6\261-9.6\))]TJ
T*
[([55])-13347.6(52.8)-2739.2(24.1)-3453.7(134/254)-4184.6(58/241)-2787.7(2.19)-336.5(\(1.70\2612.82\))-2469.1(3.5)-330.7(\(2.7\2614.9\))]TJ
T*
[([57])-13347.6(63.6)-2739.2(51.1)-3953.2(28/44)-4685.1(24/47)-3287.8(1.25)-336.5(\(0.87\2611.78\))-2469.1(8.0)-330.7(\(3.1\261-13\))]TJ
T*
[(Combined)-10848.5(48.5)-2739.2(31.2)-3453.7(351/723)-3685.1(229/733)-2787.2(1.56)-336.5(\(1.37\2611.77\))-2469.1(5.8)-330.7(\(4.5\2618.1\))]TJ
T*
[(Improvement)-337.1(rated)-335.5(by)-334.1(patients)]TJ
T*
[([40])-13347.6(53.3)-2739.2(21.4)-4452.7(8/15)-5185.1(3/14)-3288.3(2.49)-336.5(\(0.82\2617.55\))-2469.1(3.1)-330.7(\(1.5\261-80\))]TJ
T*
[([49])-13347.6(70.0)-2739.2(33.3)-4452.7(7/10)-5185.1(3/9)-3788.3(2.10)-336.5(\(0.77\2615.76\))-2469.1(2.7)-330.7(\(1.3\261-19\))]TJ
T*
[([50])-13347.6(61.1)-2739.2(55.3)-3953.2(44/72)-4685.1(42/76)-3306.7(1.1)36(1)-334.6(\(0.84\2611.45\))-2734.6(17)-334.1(\(4.6\261-10\))]TJ
T*
[([53])-13347.6(34.4)-2739.2(25.0)-3953.2(21/61)-4685.1(15/60)-3287.8(1.38)-336.5(\(0.79\2612.41\))-2747.3(1)32.1(1)-334.6(\(3.9\261-15\))]TJ
T*
[([55])-13347.6(66.9)-2739.2(32.0)-3453.7(206/308)-4184.6(97/303)-2787.7(2.09)-336.5(\(1.74\2612.51\))-2469.1(2.9)-330.7(\(2.4\2613.6\))]TJ
T*
[(Combined)-10848.5(61.4)-2739.2(34.6)-3453.7(286/466)-3685.1(160/462)-2787.2(1.78)-336.5(\(1.54\2612.05\))-2469.1(3.7)-330.7(\(3.0\2614.9\))]TJ
0 -1.9411 TD
[(CI:)-335.3(confidence)-338.8(interval.)]TJ
ET
0 0 0 1 K
0 J 0 j 0.5 w 3.864 M []0 d
/GS3 gs
351.837 175.303 m
351.837 304.552 l
351.837 278.369 m
349.212 278.369 l
351.837 304.302 m
349.212 304.302 l
351.712 252.677 m
349.212 252.677 l
351.712 200.678 m
349.212 200.678 l
351.712 175.553 m
349.212 175.553 l
351.712 226.678 m
349.212 226.678 l
S
BT
/F17 1 Tf
10 0 0 10 343.337 172.303 Tm
0 0 0 1 k
/GS4 gs
(0)Tj
-0.45 2.5142 TD
(20)Tj
0 2.6108 TD
(40)Tj
0 2.5892 TD
(60)Tj
0 2.5592 TD
(80)Tj
-0.4625 2.6 TD
(100)Tj
0 10 -10 0 320.337 186.748 Tm
[(P)40(atients with no e)30(xacerbation)]TJ
3.61 -1 TD
(with P  %)Tj
ET
[2 2 ]0 d
/GS3 gs
526.694 297.601 m
351.837 175.977 l
S
[]0 d
374.653 189.228 m
374.653 190.635 375.745 191.777 377.091 191.777 c
378.437 191.777 379.528 190.635 379.528 189.228 c
379.528 187.819 378.437 186.678 377.091 186.678 c
375.745 186.678 374.653 187.819 374.653 189.228 c
h
418.028 200.103 m
418.028 201.717 419.431 203.027 421.161 203.027 c
422.892 203.027 424.295 201.717 424.295 200.103 c
424.295 198.487 422.892 197.178 421.161 197.178 c
419.431 197.178 418.028 198.487 418.028 200.103 c
h
420.511 223.352 m
420.511 224.967 421.914 226.277 423.645 226.277 c
425.375 226.277 426.778 224.967 426.778 223.352 c
426.778 221.737 425.375 220.428 423.645 220.428 c
421.914 220.428 420.511 221.737 420.511 223.352 c
h
439.569 217.215 m
439.569 218.284 440.521 219.152 441.694 219.152 c
442.868 219.152 443.819 218.284 443.819 217.215 c
443.819 216.144 442.868 215.277 441.694 215.277 c
440.521 215.277 439.569 216.144 439.569 217.215 c
h
438.953 206.415 m
438.953 209.1 441.363 211.277 444.336 211.277 c
447.31 211.277 449.72 209.1 449.72 206.415 c
449.72 203.73 447.31 201.553 444.336 201.553 c
441.363 201.553 438.953 203.73 438.953 206.415 c
h
473.944 232.277 m
473.944 232.829 474.476 233.277 475.132 233.277 c
475.788 233.277 476.319 232.829 476.319 232.277 c
476.319 231.725 475.788 231.277 475.132 231.277 c
474.476 231.277 473.944 231.725 473.944 232.277 c
h
467.636 252.79 m
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[(pl)13.2(ac)20.4(eb)15.1(o.)-376.7(No)17.3(r)-389.3(w)12.4(as)-384.4(t)13.9(h)0(e)15.1(r)0(e)-379.1(a)0(n)15.1(y)-382(di)13.2(f)20.4(f)0(e)19.2(r)0(e)13.5(n)0(c)20.8(e)-388.1(in)-379.5(th)18.8(e)-388.1(n)0(u)15.5(m)0(b)18.1(e)0(r)-379.1(o)0(f)]TJ
0 -1.0471 TD
[(pa)15.1(ti)16.5(en)20.8(ts)-210(wh)17.3(o)-217(h)0(a)15.1(d)-217(to)-208.8(be)-212.5(w)12.4(i)0(t)16.5(h)0(d)15.5(r)0(a)19.2(w)0(n)-210.3(f)0(r)18(o)0(m)-209.5(t)0(h)13.2(e)-217.4(st)17.7(ud)21.2(ie)12.8(s)-218.2(b)0(e)20.8(c)0(a)14.7(u)0(s)20(e)]TJ
0 -1.0527 TD
[(of)-378.7(ad)20.8(ve)15.1(rs)18.4(e)-382.4(d)0(r)13.9(u)0(g)-371.4(r)0(e)19.2(a)0(c)14.7(t)0(i)16.5(o)0(n)21.2(s)0(.)-377.9(T)12.2(hu)15.5(s,)-372.2(ba)15.1(se)19.6(d)-382(o)0(n)-377.1(t)0(h)18.9(e)0(s)19.6(e)-388.1(sy)20(st)17.7(em)17.7(-)]TJ
0 -1.0471 TD
[(at)12.8(ic)18.4(al)18.5(ly)-191.7(se)19.6(ar)13.5(ch)20.8(ed)15.1(,)-199.6(r)0(e)19.2(l)0(e)18.4(v)0(a)15.1(n)0(t)-191.7(a)0(n)15.1(d)-199.9(va)20.8(li)16.5(d)-199.9(d)0(a)15.1(t)0(a)18.4(,)-199.6(or)19.6(al)-192.1(NA)13.4(C)-199(f)0(o)13.9(r)-195.8(3\261)15.5(6)]TJ
0 -1.0528 TD
[(mo)12.4(nt)18.9(hs)-429.5(se)19.6(em)17.7(s)-440.1(t)0(o)-425(b)0(e)-428.7(o)0(f)-429.9(b)0(e)15.1(n)0(e)20.8(f)0(i)17.3(t)-441.3(i)13.9(n)-438.9(pa)15.1(ti)16.5(en)20.8(ts)-431.9(w)12.4(i)0(t)16.5(h)-438.9(ch)20.8(ro)13.9(ni)18.8(c)]TJ
T*
[(br)13.9(on)21.2(ch)15.1(it)16.5(is)17.7(.)]TJ
1.0015 -1.0471 TD
[(Ho)11.6(w)-357.5(t)0(h)18.9(e)-359.7(be)15.1(ne)15.1(fi)17.3(t)-356(i)0(s)-352.2(a)0(c)14.7(h)0(i)18.9(e)0(v)20.8(e)0(d)-354.8(r)0(e)19.2(m)0(a)17.7(i)0(n)13.2(s)-360.5(un)21.2(cl)18.5(ea)14.7(r)60.2(.)-358.9(Th)17.1(er)19.2(e)-359.7(i)0(s)]TJ
-1.0015 -1.0527 TD
[(gr)13.9(ow)17.3(in)18.8(g)-291(e)0(v)15.1(i)0(d)18.8(e)0(n)15.1(c)0(e)-281.2(t)0(h)13.2(a)0(t)-283.1(C)0(O)18.3(P)0(D)-289.2(m)0(a)17.7(y)-291(be)-286.5(re)19.2(la)12.8(te)18.5(d)-291(t)0(o)-288.4(i)13.9(nc)15.1(re)19.2(as)13.9(ed)]TJ
0 -1.0471 TD
[(ox)15.5(id)18.9(at)18.5(iv)13.2(e)-393.8(a)0(n)15.1(d)-393.4(in)13.2(fl)17.3(am)17.7(ma)17.7(to)18.9(ry)-390.1(st)17.7(re)19.2(ss)-390.9([5)19.6(].)-412.5(NAC,)-407.9(as)-412.8(a)-405.2(thio)-7.8(l-)]TJ
0 -1.0527 TD
[(con)-8.4(taining)-508(compo)-7.4(und,)-509.1(may)-512.3(act)-506.2(as)-509.6(an)-502.7(anti)-8.2(oxidan)-7.4(t,)-504.3(en-)]TJ
0 -1.0471 TD
[(han)-8.4(cing)-483.8(the)-483.1(intracell)-13.5(ular)-485.4(product)-9.7(ion)-482.7(of)-481.1(glut)-7.8(athione,)-489.3(an)]TJ
0 -1.0528 TD
[(imp)-7.8(ortant)-307.2(element)-304.7(in)-299.8(pu)-7.2(lmonary)-303.1(anti)-8.2(oxidan)-7.4(t)-299.1(defence)-304.5([5].)]TJ
0 -1.0471 TD
[(It)-318.5(has)-316.9(also)-320(been)-316.8(sugges)-7.4(ted)-318.1(that)-315.5(NA)-9.4(C)-312.8(may)-318.8(have)-316.8(an)-314.9(effect)]TJ
0 -1.0528 TD
[(on)-280.4(bacterial)-284.7(adhesive)-278.3(cap)-8.8(acity)-276.8([58].)-279.8(Wheth)-7.8(er)-276.7(or)-276.3(not)-272.1(these)]TJ
0 -1.0471 TD
[(mecha)-8.2(nism)-9.8(s)-360.5(are)-363.2(respon)-7.8(sibl)-9(e)-359.7(for)-364(the)-369.3(favour)-8.2(able)-364.7(effect)-358.5(of)]TJ
0 -1.0528 TD
[(NA)-9.4(C)-403.8(o)0(n)-399.9(exacerba)-9.7(tion)-7.8(s)-400.3(and)-406.7(symp)-7.4(toms)-408.1(in)-402.2(chroni)-9(c)-399.5(bron-)]TJ
0 -1.0471 TD
[(chit)-8.2(is)-335.2(cannot)-337.8(be)-337.7(addres)-8.2(sed)-333.9(in)-334(this)-339.1(revie)-8.6(w)63.6(.)]TJ
ET
0 0 0 1 K
0 J 0 j 0.5 w 3.864 M []0 d
/GS3 gs
1 i 
336.158 641.229 m
507.908 641.229 l
507.658 641.229 m
507.658 638.979 l
336.409 641.229 m
336.409 638.979 l
S
BT
/F17 1 Tf
10 0 0 10 417.458 630.354 Tm
0 0 0 1 k
/GS4 gs
-0.0116 Tc
(80)Tj
ET
/GS3 gs
331.2 641.088 m
331.2 771.212 l
331.2 738.212 m
328.2 738.212 l
331.2 770.962 m
328.2 770.962 l
331.074 705.837 m
328.2 705.837 l
331.2 673.462 m
328.2 673.462 l
331.2 641.338 m
328.2 641.338 l
S
BT
10 0 0 10 315.784 767.354 Tm
/GS4 gs
0 Tc
(b\))Tj
ET
/GS3 gs
421.951 641.272 m
421.951 639.022 l
S
BT
10 0 0 10 500.592 630.397 Tm
/GS4 gs
(120)Tj
-16.87 0 TD
-0.0116 Tc
(40)Tj
4.515 -1.1275 TD
0 Tc
[(Cum)10(ulativ)25(e NA)30(C dose  g)]TJ
ET
/GS3 gs
421.457 658.219 m
421.457 659.392 422.408 660.344 423.581 660.344 c
424.755 660.344 425.707 659.392 425.707 658.219 c
425.707 657.045 424.755 656.094 423.581 656.094 c
422.408 656.094 421.457 657.045 421.457 658.219 c
b
0 0 0 0 k
428.57 669.2 4 -4 re
B
0 0 0 1 k
385.582 671.844 m
385.582 673.017 386.533 673.969 387.707 673.969 c
388.88 673.969 389.831 673.017 389.831 671.844 c
389.831 670.67 388.88 669.719 387.707 669.719 c
386.533 669.719 385.582 670.67 385.582 671.844 c
b
0 0 0 0 k
392.57 707.825 4 -4 re
B
0 0 0 1 k
385.457 680.344 m
385.457 681.517 386.408 682.469 387.582 682.469 c
388.755 682.469 389.707 681.517 389.707 680.344 c
389.707 679.17 388.755 678.219 387.582 678.219 c
386.408 678.219 385.457 679.17 385.457 680.344 c
b
457.206 702.344 m
457.206 703.517 458.157 704.469 459.331 704.469 c
460.505 704.469 461.456 703.517 461.456 702.344 c
461.456 701.17 460.505 700.219 459.331 700.219 c
458.157 700.219 457.206 701.17 457.206 702.344 c
b
0 0 0 0 k
392.57 729.074 4 -4 re
B
0 0 0 1 k
385.207 713.344 m
385.207 714.517 386.158 715.468 387.332 715.468 c
388.505 715.468 389.456 714.517 389.456 713.344 c
389.456 712.17 388.505 711.219 387.332 711.219 c
386.158 711.219 385.207 712.17 385.207 713.344 c
b
441.581 720.343 m
441.581 721.517 442.533 722.469 443.706 722.469 c
444.88 722.469 445.831 721.517 445.831 720.343 c
445.831 719.17 444.88 718.219 443.706 718.219 c
442.533 718.219 441.581 719.17 441.581 720.343 c
b
456.956 724.968 m
456.956 726.142 457.908 727.093 459.081 727.093 c
460.255 727.093 461.206 726.142 461.206 724.968 c
461.206 723.795 460.255 722.844 459.081 722.844 c
457.908 722.844 456.956 723.795 456.956 724.968 c
b
0 0 0 0 k
464.32 710.825 4 -4 re
B
464.195 747.324 4 -4 re
B
446.07 742.574 4 -4 re
B
392.07 756.949 4 -4 re
B
0 0 0 1 k
349.457 693.594 m
349.457 694.767 350.408 695.719 351.582 695.719 c
352.755 695.719 353.707 694.767 353.707 693.594 c
353.707 692.42 352.755 691.469 351.582 691.469 c
350.408 691.469 349.457 692.42 349.457 693.594 c
b
348.957 738.343 m
348.957 739.517 349.908 740.468 351.082 740.468 c
352.255 740.468 353.207 739.517 353.207 738.343 c
353.207 737.17 352.255 736.218 351.082 736.218 c
349.908 736.218 348.957 737.17 348.957 738.343 c
b
0 0 0 0 k
356.446 726.324 4 -4 re
B
356.196 752.324 4 -4 re
B
290.321 709.341 4 -4 re
B
129.328 641.289 m
301.077 641.289 l
244.202 641.289 m
244.202 639.039 l
300.827 641.289 m
300.827 639.039 l
186.952 641.289 m
186.952 639.039 l
129.578 641.289 m
129.578 639.039 l
S
BT
10 0 0 10 124.669 630.414 Tm
0 0 0 1 k
/GS4 gs
(10)Tj
5.7442 0.0125 TD
(15)Tj
5.75 -0.0125 TD
-0.0116 Tc
[(20)-4772(25)]TJ
ET
/GS3 gs
124.368 641.147 m
124.368 771.271 l
124.368 738.271 m
121.368 738.271 l
124.368 771.021 m
121.368 771.021 l
124.243 705.897 m
121.368 705.897 l
124.368 673.522 m
121.368 673.522 l
124.368 641.397 m
121.368 641.397 l
S
BT
10 0 0 10 115.368 638.255 Tm
/GS4 gs
0 Tc
(0)Tj
-0.45 3.1983 TD
(20)Tj
0 3.2408 TD
(40)Tj
0 3.2358 TD
(60)Tj
0 3.2733 TD
(80)Tj
0 10 -10 0 101.368 644.397 Tm
[(Pre)30(v)25(ention of an)15(y e)30(xacerbation  %)]TJ
10 0 0 10 79.703 767.413 Tm
(a\))Tj
10.675 -14.8125 TD
[(Dur)10(ation  w)10(eeks)]TJ
ET
/GS3 gs
258.207 721.36 m
258.207 722.534 259.159 723.485 260.332 723.485 c
261.506 723.485 262.457 722.534 262.457 721.36 c
262.457 720.186 261.506 719.235 260.332 719.235 c
259.159 719.235 258.207 720.186 258.207 721.36 c
b
0 0 0 0 k
286.571 711.216 4 -4 re
B
0 0 0 1 k
277.082 725.36 m
277.082 726.534 278.034 727.485 279.207 727.485 c
280.381 727.485 281.332 726.534 281.332 725.36 c
281.332 724.187 280.381 723.235 279.207 723.235 c
278.034 723.235 277.082 724.187 277.082 725.36 c
b
277.207 714.235 m
277.207 715.409 278.159 716.36 279.332 716.36 c
280.506 716.36 281.457 715.409 281.457 714.235 c
281.457 713.062 280.506 712.11 279.332 712.11 c
278.159 712.11 277.207 713.062 277.207 714.235 c
b
277.207 703.485 m
277.207 704.659 278.159 705.61 279.332 705.61 c
280.506 705.61 281.457 704.659 281.457 703.485 c
281.457 702.312 280.506 701.36 279.332 701.36 c
278.159 701.36 277.207 702.312 277.207 703.485 c
b
0 0 0 0 k
287.446 730.216 4 -4 re
B
264.196 743.591 4 -4 re
B
287.321 747.466 4 -4 re
B
287.321 757.841 4 -4 re
B
241.446 669.716 4 -4 re
B
0 0 0 1 k
236.332 658.736 m
236.332 659.909 237.284 660.86 238.457 660.86 c
239.631 660.86 240.582 659.909 240.582 658.736 c
240.582 657.562 239.631 656.611 238.457 656.611 c
237.284 656.611 236.332 657.562 236.332 658.736 c
b
277.207 673.36 m
277.207 674.534 278.159 675.485 279.332 675.485 c
280.506 675.485 281.457 674.534 281.457 673.36 c
281.457 672.187 280.506 671.236 279.332 671.236 c
278.159 671.236 277.207 672.187 277.207 673.36 c
b
277.332 681.485 m
277.332 682.659 278.284 683.61 279.457 683.61 c
280.631 683.61 281.582 682.659 281.582 681.485 c
281.582 680.312 280.631 679.36 279.457 679.36 c
278.284 679.36 277.332 680.312 277.332 681.485 c
b
0 0 0 0 k
150.447 726.966 4 -4 re
B
0 0 0 1 k
143.833 693.735 m
143.833 694.909 144.784 695.86 145.958 695.86 c
147.131 695.86 148.083 694.909 148.083 693.735 c
148.083 692.562 147.131 691.61 145.958 691.61 c
144.784 691.61 143.833 692.562 143.833 693.735 c
b
143.333 739.235 m
143.333 740.409 144.284 741.36 145.458 741.36 c
146.631 741.36 147.583 740.409 147.583 739.235 c
147.583 738.062 146.631 737.11 145.458 737.11 c
144.284 737.11 143.333 738.062 143.333 739.235 c
b
0 0 0 0 k
150.197 752.341 4 -4 re
B
BT
/F4 1 Tf
7.97 0 0 7.97 58.28 603.553 Tm
0 g
/GS2 gs
[(Fig.)-327.1(2.)-331.2(\261)-332.2(Lack)-397.7(of)-408.5(eff)14.1(ect)-406.6(of:)-408.8(a\))-400.4(study)-405.6(period)-401.5(\(12\26124)-393(weeks\);)-402.1(and)-405.3(b\))-401.4(cumulative)-403.1(dose)-397.2(of)-408.5(oral)]TJ
/F5 1 Tf
38.1193 0 TD
(N)Tj
/F4 1 Tf
0.6615 0 TD
[(-acetylcystein)9.4(e)-409.5(\(50.4\2611)13.5(00.8)-405.2(g\))-401.4(on)-408.4(the)-400.5(prevention)-401.6(of)]TJ
-38.7808 -1.0599 TD
[(exacerbation)11.1(s.)-332.4(Each)-326.6(trial)-337.3(is)-326.6(represented)-325.3(by)-330.1(two)-332.9(symbols)-324.7(\()]TJ
/F5 1 Tf
23.1746 0 TD
(i.e.)Tj
/F4 1 Tf
1.5436 0 TD
[(NAC)-323.5(\()]TJ
/F18 1 Tf
2.7528 0 TD
(h)Tj
/F4 1 Tf
0.8251 0 TD
[(\))-339.5(and)-327(placebo)-326.1(\()]TJ
/F6 1 Tf
6.1529 0 TD
(*)Tj
/F4 1 Tf
0.9958 0 TD
[(\),)-331.4(respectively\).)-324.8(Data)-335.9(from)-326.6(nine)-327.3(trials)-336.3(are)-326.2(shown.)]TJ
ET
[2 2 ]0 d
/GS3 gs
98.212 174.821 m
275.961 299.07 l
S
[]0 d
205.545 246.07 m
205.545 247.589 206.804 248.82 208.357 248.82 c
209.91 248.82 211.17 247.589 211.17 246.07 c
211.17 244.551 209.91 243.32 208.357 243.32 c
206.804 243.32 205.545 244.551 205.545 246.07 c
h
191.961 201.071 m
191.961 201.623 192.493 202.07 193.149 202.07 c
193.804 202.07 194.336 201.623 194.336 201.071 c
194.336 200.518 193.804 200.07 193.149 200.07 c
192.493 200.07 191.961 200.518 191.961 201.071 c
h
156.795 206.195 m
156.795 207.507 157.998 208.57 159.482 208.57 c
160.967 208.57 162.17 207.507 162.17 206.195 c
162.17 204.884 160.967 203.82 159.482 203.82 c
157.998 203.82 156.795 204.884 156.795 206.195 c
h
225.711 218.445 m
225.711 219.067 226.327 219.57 227.086 219.57 c
227.846 219.57 228.461 219.067 228.461 218.445 c
228.461 217.824 227.846 217.32 227.086 217.32 c
226.327 217.32 225.711 217.824 225.711 218.445 c
h
212.786 214.883 m
212.786 217.817 215.417 220.195 218.662 220.195 c
221.906 220.195 224.536 217.817 224.536 214.883 c
224.536 211.949 221.906 209.57 218.662 209.57 c
215.417 209.57 212.786 211.949 212.786 214.883 c
h
209.461 188.946 m
209.461 176.07 l
S
0 0 0 1 k
209.461 176.362 m
211.211 176.362 l
209.461 171.987 l
207.711 176.362 l
209.461 176.362 l
f*
120.462 218.57 m
107.962 218.57 l
S
108.253 218.57 m
108.253 216.82 l
103.879 218.57 l
108.253 220.32 l
108.253 218.57 l
f*
97.837 174.879 m
276.586 174.879 l
205.586 174.879 m
205.586 172.754 l
242.086 174.879 m
242.086 172.754 l
276.336 174.879 m
276.336 172.754 l
169.211 174.879 m
169.211 172.754 l
133.837 175.004 m
133.837 172.754 l
98.087 174.879 m
98.087 172.754 l
S
BT
/F17 1 Tf
10 0 0 10 95.837 164.254 Tm
/GS4 gs
(0)Tj
3.35 0.0108 TD
-0.0116 Tc
(20)Tj
3.53 -0.0108 TD
[(40)-2747(60)-2768.6(80)-2273.7(1)-11.6(0)-11.6(0)]TJ
-5.8717 -1.155 TD
0 Tc
[(P)40(atients repor)-40(ting impro)15(v)25(ement with NA)30(C  %)]TJ
ET
/GS3 gs
98.071 174.696 m
98.071 306.57 l
98.071 279.32 m
95.446 279.32 l
98.071 306.32 m
95.446 306.32 l
97.946 253.07 m
95.446 253.07 l
97.946 226.07 m
95.446 226.07 l
97.946 199.82 m
95.446 199.82 l
98.071 174.945 m
95.446 174.945 l
S
BT
10 0 0 10 89.571 171.696 Tm
/GS4 gs
(0)Tj
-0.45 2.4858 TD
(20)Tj
0 2.625 TD
(40)Tj
0 2.6892 TD
(60)Tj
0 2.6358 TD
(80)Tj
-0.4625 2.7017 TD
(100)Tj
0 10 -10 0 67.821 207.328 Tm
[(P)40(atients repor)-40(ting)]TJ
-0.9586 -1 TD
[(impro)15(v)25(ement with P  %)]TJ
/F4 1 Tf
7.97 0 0 7.97 58.28 138.387 Tm
0 g
/GS2 gs
[(Fig.)-327.1(3.)-331.2(\261)-332.2(Improveme)12.9(nt)-296.9(of)-287.6(symptoms)-287.3(\(patient)-287.2(self-asses)9.4(sment\))-289.2(with)-290.5(oral)]TJ
/F5 1 Tf
0 -1.067 TD
(N)Tj
/F4 1 Tf
0.6615 0 TD
[(-acetylcysteine)-421.4(\(NAC\))-419.2(compared)-414.5(with)-425.7(placebo)-418.5(\(P\))-425.7(in)-425(chronic)-419.7(bron-)]TJ
-0.6615 -1.0599 TD
[(chitis.)-214.2(Each)-205.7(symbol)-211.8(represent)10.9(s)-219.6(one)-206.1(trial.)-215.3(Symbol)-208.3(sizes)-212.7(are)-212.4(proportiona)11.9(l)-220.8(t)0(o)]TJ
0 -1.067 TD
[(trial)-330.1(sizes.)-332.6(Arrows)-328.2(are)-333.3(weighted)-322.7(means.)]TJ
16.282 0 TD
0.3324 Tc
(----:)Tj
3.2222 0 TD
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[(equality)68.6(.)]TJ
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0 -1.0528 TD
[(this)-549.6(trial)-553.6(were)-550(approxi)-9.7(mately)-553.9(correct)-12.1(,)]TJ
/F12 1 Tf
16.366 0 TD
0 Tw
(>)Tj
/F4 1 Tf
0.5577 0 TD
[(2,500)-549.7(patients)]TJ
-16.9237 -1.0471 TD
[(would)-243.4(have)-242.9(to)-237.2(be)-240.9(random)-9.7(ized)-239.6(to)-242.9(NAC)-242.5(or)-242.1(placeb)-8.2(o)-234.1(i)0(n)-242.9(order)]TJ
0 -1.0527 TD
[(to)-260(detect)-260.9(a)-257.2(statist)-12(ically)-262.9(signifi)-9.6(cant)-256.6(difference)-261.1(in)-260(the)-255.5(rate)-263.9(of)]TJ
0 -1.0471 TD
[(hospi)-7.4(talization)-447.5(in)-436.4(favour)-446.3(of)-441.3(NAC.)-442(Thus,)-441.2(unless)-442.2(a)-439.3(very)]TJ
0 -1.0527 TD
[(large)-281.7(trial)-286.1(is)-289.6(initiated,)-293.1(or)-287.7(relev)-8.6(ant)-283.9(data)-290.8(from)-288.2(severa)-8.6(l)-287.7(smal-)]TJ
0 -1.0471 TD
[(ler)-314(tri)-8.6(als)-313.6(can)-316.1(be)-309.2(p)-6.5(ooled)-313.9(in)-316.9(a)-308.5(met)-8.2(a-analysis)-11.9(,)-313.4(the)-312.4(econom)-8.5(ic)]TJ
0 -1.0527 TD
[(impac)-10.1(t)-333.2(o)0(f)-333.2(prevention)-344.8(of)-333.2(hospital)-9.1(ization)-337.7(due)-338.4(to)-334(exacerba)-9.7(-)]TJ
T*
[(tions)-345.5(in)-339.7(pati)-8.2(ents)-342.8(with)-347.5(chronic)-345.9(obstructi)-11.5(ve)-337.7(bronchi)-9.7(tis)-344(will)]TJ
0 -1.0471 TD
[(rema)-8.6(in)-476.2(unknow)-8.5(n.)-473.5(Fu)-6.4(rther)-482.1(end)-475(point)-8.6(s)-474.3(i)0(n)-476.2(a)-479.2(futur)-9.4(e)-473.5(cost-)]TJ
0 -1.0528 TD
[(effective)-295.3(analys)-9(is)-295.3(could)-302.5(be)-297.8(duration)-303.1(of)-293.3(disea)-8.2(se-fr)-10.2(ee)-292.6(inte)-8.2(r-)]TJ
0 -1.0471 TD
[(vals,)-644.7(saved)-648.8(days)-647.7(of)-646.2(absence)-651.2(of)-640.5(wor)-7.8(k)-643.8(and)-640(c)-6.9(osts)-645.2(of)]TJ
25.1977 66.1583 TD
[(con)-8.4(comitant)-296(medicati)-11.9(ons)-288(\(antibiotics)-297.8(and)-292.9(corticost)-11.9(eroids,)]TJ
0 -1.0471 TD
[(for)-341.2(instance\).)]TJ
1.0015 -1.0528 TD
[(Th)17.1(ir)17.3(dl)13.2(y)73.2(,)-216.6(wi)14.9(th)-208.8(re)19.2(sp)14.4(ec)20.4(t)-219.4(t)0(o)-208.8(c)0(l)12.8(i)0(n)18.9(i)0(c)18.4(a)0(l)-209.2(r)0(e)13.5(l)0(e)18.4(v)0(a)20.8(n)0(c)15.1(e)0(,)-206.4(i)0(t)-211.1(i)0(s)-210(i)0(m)15.7(p)0(o)15.5(r)0(t)17.3(a)0(n)20.8(t)]TJ
-1.0015 -1.0471 TD
[(to)-305.5(re)13.5(me)17.7(mb)18.1(er)-305.1(th)18.8(at)-305.9(th)18.9(e)-314.2(d)0(u)15.5(r)0(a)19.2(t)0(i)16.5(o)0(n)-303.1(o)0(f)-304.7(t)0(h)18.8(e)-314.2(lo)18.8(ng)15.5(es)19.6(t)-316.1(s)0(t)17.7(u)0(d)21.2(y)-313.7(in)-305.5(th)18.9(is)]TJ
0 -1.0528 TD
[(me)12(ta)18.4(-a)19.2(na)15.1(ly)18.9(si)17.7(s)-314.9(w)0(a)16.9(s)-320.6(on)21.2(ly)-311.2(6)-313.7(m)0(o)18.1(n)0(t)13.2(h)0(s)20(.)-313.4(W)37.9(i)0(t)16.5(h)0(i)18.9(n)-319.4(th)18.8(is)-306.7(li)16.5(mi)15.7(t,)-305.1(th)13.2(er)19.2(e)]TJ
0 -1.0471 TD
[(wa)16.9(s)-280.8(n)0(o)-269(e)0(v)20.8(i)0(d)13.2(e)0(n)20.8(c)0(e)-269.8(o)0(f)-270.6(a)0(n)20.8(y)-279.6(im)15.7(pa)15.1(ct)-266.1(of)-270.6(ei)18.5(th)18.9(er)-271(st)17.7(ud)15.5(y)-273.9(d)0(u)15.5(r)0(a)19.2(t)0(i)16.5(o)0(n)-269(o)0(r)]TJ
0 -1.0528 TD
[(cu)15.1(mu)18.1(la)18.4(ti)16.5(ve)-332(NA)13.4(C)-341.2(d)0(o)15.5(s)0(e)-333.2(o)0(n)-331.6(t)0(r)17.3(e)0(a)14.7(t)0(m)21.4(e)0(n)15.1(t)-344.6(ef)30.6(fi)17.3(ca)14.7(cy)-332(\(f)18(ig)18.9(.)-341.8(3\),)-344.9(and)]TJ
0 -1.0471 TD
[(there)-452.5(was)-451.7(no)-445.4(incre)-8.6(ased)-448.9(risk)-452.1(of)-447(advers)-8.2(e)-450.7(drug)-448.5(reactions.)]TJ
0 -1.0527 TD
[(How)-10.2(ever)28.7(,)-432.9(i)0(f)-438(pati)-8.2(ents)-439.5(are)-437.2(to)-436.4(take)-438.7(NAC)-441.7(on)-434(a)-439.3(preventive)]TJ
T*
[(basis)-9(,)-273.5(they)-279(are)-277.8(going)-279.3(to)-277.1(take)-279.4(it)-273.7(presum)-10.9(ably)-279(all)-274.9(the)-278.2(time)-278.8(or)]TJ
0 -1.0471 TD
[(at)-351.4(least)-357.7(every)-353.3(wi)-7.8(nter)49.5(.)-353.2(There)-351.8(is)-352.2(clear)-9(ly)-351(a)-348.3(need)-356.7(for)-352.6(studies)]TJ
0 -1.0528 TD
[(that)-457.8(look)-455(at)-453.9(both)-455(the)-454.6(benefic)-10.5(ial)-451.3(and)-452.3(adve)-9.6(rse)-449.3(effects)-451.5(of)]TJ
0 -1.0471 TD
[(regul)-8.2(ar)-333.6(treat)-11(ment)-339(over)-335.1(a)-336.9(longer)-339(perio)-8.2(d)-330.8(o)0(f)-338.9(time.)]TJ
1.0015 -1.0527 TD
[(Fi)14(na)20.8(ll)16.5(y)67.5(,)-393(th)18.9(e)-399.5(v)0(a)15.1(r)0(i)17.3(a)0(b)20.8(i)0(l)16.5(i)0(t)16.5(y)-399.1(in)-385.2(en)15.1(d)-399.1(p)0(o)21.2(i)0(n)18.8(t)0(s)-392.1(r)0(e)19.2(p)0(o)15.5(r)0(t)17.3(e)0(d)-388.9(i)0(n)-385.2(t)0(h)13.2(e)0(s)19.6(e)]TJ
-1.0015 -1.0471 TD
[(tr)17.3(ia)12.7(ls)-192.9(su)20(gg)15.5(es)19.6(ts)-192.9(un)15.5(ce)14.7(rt)17.3(ai)18.4(nt)18.9(y)-205.6(o)0(f)-190.9(t)0(r)17.3(i)0(a)18.4(l)0(i)16.5(s)0(t)17.7(s)-206.8(ab)20.8(ou)15.5(t)-202.3(w)0(h)17.3(i)0(c)18.5(h)-205.6(en)20.8(d)-205.6(p)0(o)21.2(i)0(n)18.9(t)]TJ
0 -1.0527 TD
-0.0178 Tc
[(i)-17.8(s)-358.6(t)-17.8(h)1.1(e)-366.1(m)-17.8(os)-17.8(t)-358.6(r)-17.8(el)-17.8(ev)-17.8(an)-17.8(t)-351.8(i)-17.8(n)-357.5(t)-17.8(hi)-17.8(s)-358.6(c)-17.8(li)-17.8(ni)-17.8(ca)-17.8(l)-357.9(s)-17.8(et)-17.8(ti)-17.8(ng)-17.8(.)-354.7(P)-17.8(re)-17.8(ve)-17.8(nt)-17.8(io)-17.8(n)-355.1(o)-17.8(f)]TJ
0 -1.0471 TD
0 Tc
[(ex)15.1(ac)14.7(er)19.2(ba)20.8(ti)16.5(on)15.5(,)-398.7(f)0(o)19.6(r)-400.7(in)18.9(st)17.7(an)15.1(ce)20.4(,)-398.7(w)0(a)16.9(s)-400.3(no)21.2(t)-401.5(r)0(e)19.2(p)0(o)15.5(r)0(t)17.3(e)0(d)-388.9(i)0(n)-390.9(a)0(l)18.4(l)-401.5(tr)17.3(ia)18.4(ls)17.7(.)]TJ
0 -1.0528 TD
[(Al)14.9(so)14.4(,)-193.9(t)0(h)18.9(e)0(r)13.5(e)-200.3(w)12.4(a)0(s)-190.9(n)0(o)-189.3(e)0(v)15.1(i)0(d)18.9(e)0(n)20.8(c)0(e)-190.1(t)0(h)13.2(a)0(t)-186.4(t)0(h)13.2(e)-194.7(be)15.1(ne)20.8(fi)17.3(t)-202.3(f)0(r)18(o)0(m)-192.5(N)12.4(AC)-192.3(wa)16.9(s)]TJ
0 -1.0471 TD
[(re)13.5(la)18.4(te)18.4(d)-228.4(t)0(o)-220.2(m)0(a)17.7(j)0(o)18.8(r)-230(ch)15.1(an)20.8(ge)15.1(s)-223.9(i)0(n)-220.2(l)0(u)18.9(n)0(g)-223.5(f)0(u)19.6(n)0(c)15.1(t)13.9(io)13.2(n.)-217.4(T)12.2(h)0(u)15.5(s)-229.6(pa)20.8(ra)13.5(me)17.7(te)18.4(rs)]TJ
0 -1.0527 TD
[(of)-196.6(lu)18.9(ng)-195(fu)19.6(nc)15.1(ti)16.5(on)-189.3(ma)12(y)-199.9(b)0(e)-195.4(s)0(u)20(r)0(r)18(o)0(g)15.5(a)0(t)18.5(e)-206(en)20.8(d)-205.6(p)0(o)21.2(i)0(n)13.2(t)13.9(s)-206.8(f)0(o)19.6(r)-201.5(es)13.9(ti)16.5(ma)17.7(ti)16.5(on)]TJ
0 -1.0471 TD
[(of)-270.6(th)18.9(e)-280(e)0(f)24.9(f)0(i)17.3(c)0(a)20.4(c)0(y)-269.4(o)0(f)-270.6(m)0(u)18.1(c)0(o)15.1(l)0(y)18.8(t)0(i)16.5(c)-280(ag)20.8(en)15.1(ts)-266.9(in)-271.4(CO)18.3(PD)12.4(.)-273.5(T)0(h)17.1(e)-280(au)15.1(th)18.8(or)19.6(s)]TJ
0 -1.0528 TD
[(be)15.1(li)16.5(ev)20.8(e,)-399.9(ho)21.2(we)16.9(ve)15.1(r)37.5(,)-404.4(th)18.9(at)18.5(,)-404.4(i)0(n)-402.3(t)0(h)18.9(i)0(s)-397.8(c)0(l)18.5(i)0(n)18.9(i)0(c)18.4(a)0(l)-402.7(c)0(o)20.8(n)0(t)18.8(e)0(x)15.1(t)0(,)-396.2(i)0(m)15.7(p)0(r)19.6(o)0(v)15.5(e)0(-)]TJ
0 -1.0471 TD
[(me)12(nt)-311.2(of)-310.4(sy)20(mp)18.1(to)18.9(ms)11.2(,)-313.4(a)0(s)-316.1(j)13.9(ud)15.5(ge)15.1(d)-319.4(b)0(y)-308.8(t)0(h)18.8(e)-319.8(pa)20.8(ti)16.5(en)15.1(ts)-312.4(th)18.8(em)17.7(se)19.6(lv)13.2(es)19.6(,)]TJ
0 -1.0527 TD
[(ma)12(y)-530(b)0(e)-525.5(a)0(n)-519.8(i)0(m)15.7(p)0(o)15.5(r)0(t)17.3(a)0(n)20.8(t)-538.1(en)20.8(d)-530(p)0(o)15.5(i)0(n)18.8(t)0(.)-527.1(O)12.4(ne)-525.5(in)-521.8(fo)13.9(ur)-521(pa)15.1(ti)16.5(en)20.8(ts)]TJ
0 -1.0471 TD
[(re)13.5(po)21.2(rt)17.3(ed)-525.5(im)15.7(pr)19.6(ov)15.5(em)17.7(en)15.1(t)-526.7(o)0(f)-526.7(t)0(h)18.8(e)0(i)18.4(r)-531.6(sy)14.4(mp)18.1(to)18.9(ms)-523.7(wh)17.3(il)16.5(e)-530.4(t)0(a)18.4(k)0(i)13.2(n)0(g)]TJ
0 -1.0528 TD
[(NA)13.4(C)-278.6(c)0(o)20.8(m)0(p)18.1(a)0(r)13.5(e)0(d)-263.7(w)0(i)14.9(t)0(h)-265.7(t)0(h)18.9(o)0(s)14.4(e)-274.3(re)19.2(ce)14.7(iv)18.9(in)18.9(g)-273.9(p)0(l)13.2(a)0(c)20.4(e)0(b)15.1(o)-273.9(\(6)19.6(1.)15.9(4)]TJ
/F5 1 Tf
20.3153 0 TD
[(ve)14.7(rs)18.8(us)]TJ
/F4 1 Tf
-20.3153 -1.0471 TD
[(34)15.5(.6)15.9(%\))17.3(.)-347.5(I)0(t)-341.2(i)0(s)-340.8(n)0(o)21.2(t)-350.3(kn)15.5(ow)17.3(n)-347.9(e)0(x)20.8(a)0(c)14.7(t)0(l)16.5(y)-347.9(wh)17.3(at)-340.1(th)18.9(e)-348.3(e)0(n)15.1(d)-347.9(po)21.2(in)13.2(t)-344.6(")0(i)15.9(m)0(-)]TJ
0 -1.0527 TD
[(pr)13.9(ov)21.2(em)12(en)20.8(t)-498.2(o)0(f)-492.5(s)0(y)20(m)0(p)12.4(t)13.9(om)12.4(s")-489.4(me)17.7(an)15.1(s)-497(t)0(o)-487.6(t)0(h)13.2(e)-496.3(da)15.1(il)22.2(y)-501.5(l)0(i)16.5(f)0(e)-487.2(o)0(f)-492.5(a)]TJ
0 -1.0471 TD
[(pa)15.1(ti)16.5(en)20.8(t)-338.9(w)12.4(it)16.5(h)-336.5(C)11.6(OP)12.4(D)12.4(.)-336.1(Qu)17.3(al)18.5(it)16.5(y)-330.8(o)0(f)-327.5(l)0(i)16.5(f)0(e)19.2(,)-336.1(fo)19.6(r)-338.1(i)13.9(ns)14.4(ta)18.4(nc)15.1(e,)-320.2(wa)16.9(s)-337.7(n)0(o)21.2(t)]TJ
0 -1.0528 TD
[(re)13.5(po)21.2(rt)17.3(ed)-320.6(in)-322.6(an)20.8(y)-330.8(t)0(r)17.3(i)0(a)18.4(l)0(.)-322.2(I)0(t)-318.5(m)0(i)15.7(g)0(h)15.5(t)-327.5(be)-320.6(sp)20(ec)14.7(ul)18.9(at)18.4(ed)-320.6(th)18.8(at)18.4(,)-330.4(i)0(n)-316.9(t)0(h)13.2(e)0(s)19.6(e)]TJ
0 -1.0471 TD
[(pa)15.1(ti)16.5(en)20.8(ts)17.7(,)-250.8(i)0(m)15.7(p)0(r)13.9(o)0(v)21.2(e)0(m)17.7(e)0(n)15.1(t)-253.5(of)-242.1(sy)20(mp)18.1(to)13.2(m)13.2(s)-252.3(in)18.9(di)13.2(ca)20.4(te)18.4(s)-252.3(a)0(n)-246.6(i)13.9(nc)15.1(re)19.2(as)13.9(ed)]TJ
0 -1.0528 TD
[(le)12.8(ve)20.8(l)-327.5(o)0(f)-316.1(s)0(a)19.6(t)0(i)16.5(s)0(f)18.4(a)0(c)14.7(t)13.9(io)13.2(n)-319.4(o)0(r)-316.1(a)-325.5(be)15.1(tt)16.5(er)-310.8(qu)15.5(al)18.5(it)16.5(y)-325.1(o)0(f)-316.1(l)0(i)16.5(f)0(e)19.2(.)]TJ
1.0015 -1.0471 TD
[(In)-338.9(co)15.1(nc)20.8(lu)18.9(si)17.7(on)15.5(,)-347.5(b)0(a)20.8(s)0(e)19.6(d)-347.9(on)-337.3(da)20.8(ta)-340.1(fr)18(om)-340.4(sy)20(st)17.7(em)17.7(at)18.4(ic)12.8(al)18.4(ly)-334(se)13.9(ar)30.6(-)]TJ
-1.0015 -1.0527 TD
[(ch)15.1(ed)-662(ra)19.2(nd)15.5(om)18.1(iz)18.4(ed)-662(co)15.1(nt)18.9(ro)19.6(ll)16.5(ed)-662(tr)17.3(ia)18.5(ls)17.7(,)-671.9(t)0(r)17.3(e)0(a)14.7(t)0(m)15.7(e)0(n)20.8(t)-668.9(fo)13.9(r)-668.2(3)0(\261)15.5(6)]TJ
0 -1.0471 TD
[(mo)12.4(nt)18.9(hs)-253.1(w)12.4(i)0(t)16.5(h)-262.5(or)19.6(al)]TJ
/F5 1 Tf
6.9026 0 TD
(N)Tj
/F4 1 Tf
0.6544 0 TD
[(-a)13.5(ce)20.4(ty)18.8(lc)12.8(ys)20(te)18.4(in)18.8(e)-262.9(i)0(n)-248.6(p)0(a)15.1(t)0(i)16.5(e)0(n)20.8(t)0(s)-255.5(w)12.4(it)16.5(h)-262.5(c)0(h)20.8(r)0(o)13.9(n)0(i)18.8(c)]TJ
-7.557 -1.0527 TD
[(br)13.9(on)21.2(ch)15.1(it)16.5(is)-340.8(is)-340.8(as)19.6(so)14.3(ci)18.4(at)18.5(ed)-337.7(wi)14.9(th)-339.7(a)-354(s)0(t)17.7(a)0(t)18.5(i)0(s)17.7(t)0(i)16.5(c)0(a)20.4(l)0(l)16.5(y)-347.9(si)17.7(gn)15.5(if)17.3(ic)18.5(an)15.1(t)-350.3(d)0(e)20.8(-)]TJ
0 -1.0471 TD
[(cr)13.5(ea)20.4(se)-407.2(in)-407.9(th)18.8(e)-416.6(r)0(i)17.3(s)0(k)-406.7(o)0(f)-407.2(e)0(x)20.8(a)0(c)14.7(e)0(r)19.2(b)0(a)15.1(t)0(i)16.5(o)0(n)21.2(s)0(,)-406.4(a)0(n)15.1(d)-410.5(an)-406(ev)15.1(en)-406(gr)19.6(ea)14.7(te)18.4(r)]TJ
0 -1.0528 TD
[(ef)24.9(fe)19.2(ct)-527.8(on)-530.8(br)19.6(on)15.5(ch)20.8(it)16.5(ic)-527.8(sy)20(mp)12.4(to)18.9(ms)16.9(.)-535.3(T)0(h)17.1(i)0(s)-528.6(t)0(r)17.3(e)0(a)20.4(t)0(m)15.7(e)0(n)15.1(t)-538.1(i)13.9(s)-536.9(we)16.9(ll)]TJ
0 -1.0471 TD
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T*
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T*
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