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[(In)-253.2(con)-16(t)10.5(ras)-16(t)10.7(,)-255.6(drug)-16(s)]TJ
-17.5325 -1.1116 TD
[(adm)-15.9(i)9.3(nis)-15.9(t)10.8(ered)-316.5(via)-317.7(i).2(ntr)-15.9(a)9.6(musc)-15.9(u)9.5(l).2(ar)-316.5(inje)-15.9(c)8.4(tion)-15.9(s)-300.1(la)-15.9(r)9.6(g).3(el)-15.9(y)-300.4(byp)-15.9(a)9.5(s).5(s)-316.3().4(rst)-15.9(-)]TJ
0 -1.1174 TD
-.0156 Tc
[(pas)-15.6(s)-196(h)-15.6(e)9.8(pati)-15.6(c)-197.6(met)-15.6(a)9.7(bol)-15.6(i)10.7(s).8(m.)-209.1(Al)-15.6(t)10.7(hou)-15.6(g)11(h)-206.8(ex)-15.6(t)10.9(r).6(ah)-15.6(e)9.8(p).6(ati)-15.6(c)-197.6(or)-15.6(g)11(a)-.6(ns)-212.3(may)-212.5(be)]TJ
0 -1.1116 TD
-.0159 Tc
[(in)-15.9(v)10.7(o).3(lve)-15.9(d)-422.4(in)-431.7(t)-15.9(h)10.6(e)-432.9(c)-.9(l)-15.9(e)9.4(aran)-15.9(c)9.5(e)-432.9(of)-437.4(drugs)-437.3(del)-15.9(i)10.4(vere)-15.9(d)-422.4(v).3(ia)-438.6(alter)-15.9(n)10.7(ati)-15.9(v)10.6(e)]TJ
T*
[(ro)-15.9(u)10.7(t).2(es)-327.8(su)-15.9(c)9.5(h)-322.3(a)-15.9(s)-312.8(i)-15.9(n)10.6(tra)-15.9(m)8.3(uscu)-15.9(l)10.6(a)-.9(r)-328(i).2(nj)-15.9(e)9.4(c)-.9(tio)-15.9(n)10.7(s).5(,)-324.6(t)-15.9(h)10.6(e)-329.2(pathw)-15.9(a)8.7(ys)-327.8(of)-328(thei)-15.9(r)]TJ
0 -1.1174 TD
[(met)-15.9(a)9.4(boli)-15.9(s)10.8(m)-254.4(a)-.9(re)-254.3(la)-15.9(r)9.6(g).3(ely)-253.1(u)-15.9(n)10.7(e)-.9(xpl)-15.9(o)10.6(r).3(ed)-15.9(.)-239.3(I).3(n)-253.1(a)-.9(d)-15.9(d)10.7(iti)-15.9(o)10.6(n).3(,)-255.5(litt)-15.9(l)10.4(e)-254.3(is)-252.9(kno)-15.9(w)9.8(n)]TJ
0 -1.1116 TD
-.0156 Tc
[(abo)-15.6(u)11(t)-276(t).5(h)-15.6(e)-266.6(dif)-15.6(f)11.1(ere)-15.6(n)9.8(ces)-275.7(i)-15.6(n)-265.6(the)-282.8(metab)-15.6(o)11(lis)-15.6(m)-266.5(o).6(f)-275.9(d).6(r)-15.6(u)11(gs)-275.7(a)-15.6(d)9.8(mini)-15.6(s)11.1(t).5(er)-15.6(e)9.9(d)]TJ
T*
0 Tc
[(v)16.2(i)0(a)-285.7(o)0(r)26.6(a)15(l)-300.7(r)16.2(o)16.2(u)0(t)26.5(e)15(s)-300.4(v)16.2(e)15(r)0(s)26.8(u)16.2(s)-300.4(i)16.1(nt)26.5(r)16.2(a)15(m)15(u)16.2(sc)25.6(u)16.2(l)16.1(ar)-291.3(i)16.1(n)16.2(j)16.1(e)15(ct)25.3(i)16.1(o)16.2(n)16.2(s)0(.)-286.6(M)15.3(or)26.6(e)15(o)16.2(ve)25.4(r)16.2(,)-297.2(th)26.5(e)]TJ
0 -1.1174 TD
-.0158 Tc
[(pat)-15.8(h)10.7(way)-15.8(s)-426.7(o)-15.8(f)-432.7(drug)-443.1(meta)-15.8(b)9.6(oli)-15.8(s)10.9(m)-444.3(a)-.8(fter)-443.1(in)-15.8(t)10.7(r).4(amu)-15.8(s)11(c)-.8(ul)-15.8(a)9.5(r)-443.1(inje)-15.8(c)8.5(tion)-15.8(s)]TJ
0 -1.1116 TD
[(may)-281.8(yi)-15.8(e)9.5(l).3(d)-281.8(i).3(ns)-15.8(i)10.9(ght)-15.8(s)-271.4(i).3(nto)-281.8(t).3(h)-15.8(e)9.6(ir)-281.8(ef)-15.8(c)9.8(acy)-281.8(and)-281.8(s)-15.8(a)9.8(f).4(ety)-281.8(p).4(r)-15.8(o)10.8(le)-15.8(s)9.8(.)]TJ
1.0137 -1.1116 TD
0 Tc
[(Previously,)-366.8(we)-367.1(characterized)-368.2(RPV)-367.9(metabolism)-367.3(after)-365(oral)]TJ
-1.0137 -1.1116 TD
[(dosing)-369.4(and)-373.1(identied)-369.6(seven)-376.3(metabolites:)-375.5(four)-367.2(mono-)-369.6(or)-370.8(di-)]TJ
0 -1.1174 TD
[(hydroxylated)-476.6(metabolites,)-481.4(one)-476.8(N-linked)-477.6(RPV)-477.3(glucuronide)]TJ
0 -1.1116 TD
[(conjugate,)-224.5(and)-223.3(two)-223.2(O-linked)-224.2(RPV)-223.9(glucuronides)-222.9(produced)-224.2(via)]TJ
T*
[(glucuronidation)-572.3(of)-566.6(mono-)-571.2(and)-568.9(dihydroxymethyl)-572.2(metabo-)]TJ
0 -1.1174 TD
(lites.)Tj
7.3823 0 0 6.5614 81.0141 214.3559 Tm
(9)Tj
9.843 0 0 9.843 87.3637 209.9905 Tm
[(In)-267.1(the)-269.5(same)-272.7(study,)-268.1(we)-269.2(elucidated)-275.2(the)]TJ
/F5 1 Tf
14.9522 0 TD
[(in)-267.3(vitro)]TJ
/F4 1 Tf
3.2139 0 TD
[(routes)-272.6(of)]TJ
-20.7407 -1.1116 TD
[(RPV)-523.4(metabolism)-522.8(by)-514.8(using)-523.8(human)-520.5(liver)-519.5(microsomes)-522.4(and)]TJ
T*
[(cDNA-expressed)-408.1(enzyme)-403(assays.)-403.4(These)-400.5(analyses)-403.7(indicated)]TJ
0 -1.1174 TD
[(that)-265(CYP3A4)-262.7(and)-263.6(CYP3A5)-262.7(are)-264.8(primarily)-266.1(responsible)-261.9(for)-262.4(the)]TJ
0 -1.1116 TD
[(oxidative)-283.3(metabolism)-280.9(of)-278.6(RPV.)-279.2(In)-284.4(addition,)-278.7(it)-278.9(was)-281.6(found)-276.2(that)]TJ
T*
[(RPV)-264.2(and)-263.6(a)-267.2(monomethylhydroxylated)-266.8(metabolite)-269.7(of)-261.4(RPV)-264.2(are)]TJ
0 -1.1174 TD
[(primarily)-306.4(metabolized)-312.1(via)-309.9(glucuronidation)-307.3(by)-301.7(UGT1A4)-309.9(and)]TJ
0 -1.1116 TD
[(UGT1A1,)-307.6(respectively.)]TJ
7.3823 0 0 6.5614 154.8283 137.6504 Tm
(9)Tj
9.843 0 0 9.843 161.5181 133.285 Tm
[(However,)-308.9(a)-301.8(role)-305.2(for)-302.7(these)-307.3(enzymes)]TJ
-10.1083 -1.1116 TD
[(in)-215.4(metabolizing)-220(a)-215.4(drug)-211.7(delivered)-215.2(via)-217.7(an)-216.5(injection)-214.3(is)-215.2(undened)]TJ
T*
[(and)-396.1(the)-396.3(genes)-399.3(encoding)-397.2(enzymes)-398.1(CYP3A5,)-398.6(UGT1A1,)-399.8(and)]TJ
0 -1.1174 TD
[(UGT1A4)-281.1(are)-287.8(polymorphic.)]TJ
1.0137 -1.1116 TD
[(In)-445.7(this)-448(work,)-452.2(we)-447.7(investigated)-454.8(the)-448.1(metabolism)-448(of)-451.4(orally)]TJ
-1.0137 -1.1116 TD
[(administered)-294.6(RPV)-287.3(as)-285.4(well)-288.9(as)-285.4(long-acting)-291.3(RPV)-287.3(delivered)-290.1(via)]TJ
0 -1.1174 TD
[(intramuscular)-359(injections)-359.3(in)-353.7(HIV)-356.3(Prevention)-353.2(Trials)-360.3(Network)]TJ
0 -1.1116 TD
[(076)-383.4(\(HPTN)-388.4(076\))-390.3(study)-385.6(participants.)-389.1(The)-385.8(HPTN)-387.3(076)-383.4(study)]TJ
25.504 67.9242 TD
[(was)-218.3(a)-215.4(multi-site,)-213.1(double-blinded,)-217.4(two-arm)-218.4(\(2:1\),)-216.4(randomized,)]TJ
0 -1.1174 TD
[(phase)-272.6(II)-267.1(clinical)-277.8(trial)-266.2(conducted)-272.7(to)-267.3(investigate)-275.1(the)-269.5(safety)-273.8(and)]TJ
0 -1.1116 TD
[(acceptabil)-11.5(ity)-262.7(of)-261.4(a)-261.4(long-acting)-268.2(injectable)-269.6(\(1,200)-164.4(mg)-268.4(dosed)-259.9(six)]TJ
T*
[(times)-480.3(at)-481.5(8)-473.4(week)-479.9(intervals\))-480(for)-481.3(use)-476.6(in)-474.6(HIV)-483.1(PrEP.)]TJ
7.3823 0 0 6.5614 519.3636 696.6423 Tm
(10)Tj
9.843 0 0 9.843 531.496 692.277 Tm
(HIV-)Tj
-22.1922 -1.1116 TD
[(uninfected)-256.6(women)-250.7(\()]TJ
/F5 1 Tf
8.0233 0 TD
(n)Tj
/F7 1 Tf
.6624 0 TD
(=)Tj
/F4 1 Tf
.72 0 TD
[(136\))-252(were)-249.5(recruited)-249.7(across)-256.2(four)-246.2(cities)]TJ
-9.4056 -1.1174 TD
[(for)-239.4(this)-234.9(study:)-237.1(Bronx,)-234.6(New)-236.6(York;)-236.9(Newark,)-238.7(New)-236.6(Jersey;)-240.1(Cape)]TJ
0 -1.1116 TD
[(Town,)-280.6(South)-276.2(Africa;)-281.8(and)-275.2(Harare,)-285(Zimbabwe.)-277.2(Initial)-280.1(ndings)]TJ
T*
[(from)-310.8(this)-304(study)-304.9(have)-306.2(demonstrated)-306(the)-309.9(high)-304(acceptability)-308.8(of)]TJ
0 -1.1174 TD
[(long-acting)-469.8(RPV)-465.8(for)-464(long-acting)-464.1(injectable)-471.2(PrEP)-460.3(delivery)]TJ
0 -1.1116 TD
[(over)-224.4(both)-223.4(oral)-224.5(and)-223.3(vaginal)-223.4(methods)-228.9(among)-221(study)-224.3(participants)]TJ
T*
[(\(U.S.)-287.3(and)-286.7(African)-281.7(women\).)]TJ
7.3823 0 0 6.5614 421.3416 619.9368 Tm
(10)Tj
9.843 0 0 9.843 431.4897 615.5715 Tm
[(In)-284.4(addition,)-284.5(the)-286.8(safety)-285.3(and)-286.7(tol-)]TJ
-12.032 -1.1174 TD
[(erability)-404.4(of)-393.8(long-acting)-400.7(RPV)-402.5(has)-395.9(been)-398.4(reported)-402.9(recently.)]TJ
7.3823 0 0 6.5614 544.8187 608.9951 Tm
(11)Tj
9.843 0 0 9.843 313.0582 593.6313 Tm
[(The)-241.8(goals)-231.2(of)-238.3(this)-234.9(work)-235.6(were)-238(to)-232.7(chara)-9(cterize)-237.2(RPV)-235.4(metabolites)]TJ
/F5 1 Tf
0 -1.1116 TD
[(in)-203.9(vivo)]TJ
/F4 1 Tf
2.8626 0 TD
[(by)-198(using)-201.3(plasma,)-203.6(rectal)-206.2(uid,)-197.9(cervicovaginal)-205.9(uid,)-203.6(and)]TJ
-2.8626 -1.1116 TD
[(va)13.9(gi)20.7(na)19.7(l)-364.1(t)0(i)20.6(s)0(s)15.5(u)0(e)-354.7(s)0(a)19.9(m)0(p)19.6(l)0(e)19.6(s)-369.5(ob)20.8(ta)19.6(in)20.7(ed)-354.7(fr)15.2(om)-354.8(HP)20.1(TN)-355.6(07)20.8(6)-364(s)0(t)15.1(u)0(d)20.8(y)-364(pa)19.7(r-)]TJ
0 -1.1174 TD
[(ti)14.8(ci)19.5(pa)19.7(nt)20.7(s,)-597.6(an)19.7(d)-611.6(t)0(o)-595.6(i)0(n)15(v)0(e)19.7(s)0(t)20.9(i)0(g)20.7(a)0(t)19.5(e)-612.8(th)20.7(e)-607(p)0(r)15.1(e)0(s)19.9(e)0(n)19.7(c)0(e)-597.8(o)0(f)-601.2(v)0(a)19.7(r)0(i)20.7(a)0(n)19.7(t)0(s)-601.1(o)0(f)]TJ
/F5 1 Tf
0 -1.1116 TD
[(CY)14.2(P3)19.6(A4)]TJ
/F4 1 Tf
3.3925 0 TD
(,)Tj
/F5 1 Tf
.6912 0 TD
[(CY)20(P3)19.6(A5)]TJ
/F4 1 Tf
3.3867 0 TD
(,)Tj
/F5 1 Tf
.6969 0 TD
[(UG)19.1(T1)21(A1)]TJ
/F4 1 Tf
3.5422 0 TD
.4412 Tc
[(,a)441.2(n)460.9(d)]TJ
/F5 1 Tf
2.5631 0 TD
0 Tc
[(UG)19.1(T1)21(A4)]TJ
/F4 1 Tf
3.9972 0 TD
[(by)-434.2(us)21(in)20.7(g)-444.6(n)0(e)19.7(x)0(t)20.7(-)]TJ
-18.2698 -1.1116 TD
[(ge)13.9(ne)19.7(ra)19.7(ti)20.6(on)-221.1(ta)19.6(rg)15.1(et)19.6(ed)-222.2(se)19.9(qu)20.8(en)19.7(ci)13.8(ng)20.8(.)-228.1(A)0(f)14.2(t)0(e)19.6(r)-231.5(th)20.7(e)-232.6(i)0(n)20.7(j)0(e)13.8(c)0(t)19.5(i)0(o)20.7(n)-231.5(ph)20.8(as)19.9(e,)-224.6(tw)19.8(o)]TJ
0 -1.1174 TD
[(me)18.4(ta)13.8(bo)20.8(li)20.6(te)19.5(s,)-332.6(2-)20.9(hy)20.8(dr)15.1(ox)20.8(ym)19.6(et)19.5(hy)20.8(l)-341(R)0(P)20(V)-347.6(an)19.7(d)-340.9(R)0(P)20(V)-341.8(N-)20(gl)20.7(uc)13.9(ur)20.9(on)20.8(id)20.7(e)]TJ
0 -1.1116 TD
[(we)13(re)-285.6(de)19.7(te)19.5(ct)19.5(ed)-285.6(in)-284.5(pl)14.9(as)19.9(ma)-286.8(sa)19.9(mp)19.6(le)19.5(s)-294.6(o)0(f)-290.1(t)0(h)20.7(e)-296(pa)19.7(rt)20.7(ic)19.5(ip)15(an)19.7(ts)20.9(.)-297.2(I)0(n)-284.4(a)0(d)19.7(d)0(i)20.7(-)]TJ
T*
[(ti)14.8(on)20.8(,)-349(R)0(P)20(V)-353.3(N-)14.2(gl)20.7(uc)19.7(ur)20.9(on)20.8(id)20.7(e)-353.6(w)0(a)18.8(s)-352.2(de)19.7(te)13.8(ct)19.6(ab)19.7(le)-343.3(in)-342.1(re)19.7(ct)19.6(al)-343.3(u)21(id)20.7(,)-354.8(c)0(e)18.5(r)0(-)]TJ
0 -1.1174 TD
[(vi)14.9(co)19.7(va)19.7(gi)20.7(na)19.7(l)-427.4()0(u)21(i)0(d)15(,)-423.9(an)19.7(d)-427.3(v)0(a)19.7(g)0(i)14.9(n)0(a)19.7(l)-427.4(ti)20.6(ss)21.2(ue)19.7(.)-429.6(F)0(r)21(o)0(m)-418.1(n)0(e)19.7(x)0(t)20.7(-)0(g)15.1(e)0(n)19.7(e)0(r)19.7(a)0(t)19.5(i)0(o)20.7(n)]TJ
0 -1.1116 TD
[(ta)13.8(rg)20.9(et)19.5(ed)-481.4(se)19.9(qu)20.8(en)19.7(ci)19.5(ng)-480.3(an)19.7(al)19.5(ys)21(es)14.1(,)-487.2(f)0(o)20.9(u)0(r)-480.2(m)15(is)15.1(se)19.9(ns)21(e)-491.8(v)0(a)19.7(r)0(i)20.7(a)0(n)19.7(t)0(s)-480.2(w)0(e)18.8(r)0(e)]TJ
T*
[(de)13.9(te)19.5(ct)19.6(ed)-320.1(fo)20.9(r)]TJ
/F5 1 Tf
5.0916 0 TD
[(CY)20(P3)19.6(A4)]TJ
/F4 1 Tf
3.7265 0 TD
[(wh)20(er)14(ea)18.5(s)]TJ
/F5 1 Tf
3.5537 0 TD
[(UG)19.1(T1)21(A4)]TJ
/F4 1 Tf
3.882 0 TD
[(ex)19.7(hi)20.7(bi)14.9(te)19.5(d)-329.4(e)0(i)19.6(g)0(h)20.8(t)-329.5(mi)19.5(s-)]TJ
-16.2539 -1.1174 TD
[(se)14.1(ns)21(e)-440(v)0(a)19.7(r)0(i)20.7(a)0(n)19.7(t)0(s)20.9(.)-441.2(In)-422.6(su)15.3(m)15(,)-441.2(re)19.7(su)21(lt)20.6(s)-438.6(f)0(r)20.9(o)0(m)-429.6(t)0(h)20.7(i)0(s)-428.3(s)0(t)20.9(u)0(d)20.8(y)-438.8(yi)20.7(el)19.5(d)-438.8(n)0(o)20.8(v)0(e)19.7(l)]TJ
0 -1.1116 TD
[(in)15(si)20.9(gh)20.8(ts)-261.3(in)20.7(to)-261.5(th)20.7(e)-273(m)0(e)18.4(t)0(a)19.5(b)0(o)20.8(l)0(i)20.6(s)0(m)-262.4(o)0(f)-261.4(l)0(o)20.7(n)0(g)20.8(-)0(a)14(c)0(t)19.5(i)0(n)20.7(g)-271.8(RP)20(V.)]TJ
/F1 1 Tf
8.9663 0 0 8.9663 313.0582 427.4078 Tm
[(Materials)-339(and)-331.9(Methods)]TJ
/F9 1 Tf
0 -2.0423 TD
[(Chemicals)-339.5(and)-329.4(reagents)]TJ
/F4 1 Tf
9.843 0 0 9.843 323.0361 392.655 Tm
[(RPV)-563.7(was)-558.1(provided)-563(through)-560.7(the)-557.5(National)-565.3(Institutes)-559.4(of)]TJ
-1.0137 -1.1116 TD
[(Healt)-9(h)-220(AIDS)-230.6(Reagents)-226.4(Progra)-7.5(m.)-224.6(2-Hydroxymethyl)-227.3(RPV)-229.7(and)]TJ
T*
[(rilpiv)-7(irine-d)]TJ
7.3823 0 0 6.5614 360.8503 369.1274 Tm
(6)Tj
9.843 0 0 9.843 369.8645 370.7716 Tm
(\(RPV-d)Tj
7.3823 0 0 6.5614 400.4219 369.1274 Tm
(6)Tj
9.843 0 0 9.843 404.107 370.7716 Tm
[(\))-536.7(were)-537.5(obtained)-541.3(from)-535.5(Toronto)-538.9(Re-)]TJ
-9.2501 -1.1174 TD
[(search)-292.1(Chemicals)-292.2(\(Toronto,)-284.2(ON,)-289.6(Canada\).)-286.3(All)-286.7(solvents)-292.1(used)]TJ
0 -1.1116 TD
[(were)-762.1(high-performance)-760.8(liquid)-755.8(chromatography)-757.5(\(HPLC\))]TJ
T*
[(grade)-376.4(and)-367.3(obtained)-374.3(from)-368.4(Fisher)-370.4(Scientic)-370.6(\(Hampton,)-372.7(NH\),)]TJ
0 -1.1174 TD
[(unless)-284(otherwise)-283.9(specied.)]TJ
/F9 1 Tf
8.9663 0 0 8.9663 313.0582 303.1369 Tm
[(Clinical)-340.5(samples)]TJ
/F4 1 Tf
9.843 0 0 9.843 323.0361 286.696 Tm
[(Th)19.6(e)-238.4(H)0(P)20.1(T)0(N)-228.9(0)0(7)20.8(6)-237.2(st)15.1(ud)20.8(y)-237.2(w)0(a)18.8(s)-237.1(ca)18.5(rr)20.9(ie)19.6(d)-237.2(o)0(u)20.8(t)-237.4(as)-227.8(re)19.7(po)15.1(rt)20.7(ed)-228(by)-226.8(To)19.6(ll)20.6(ey)]TJ
/F5 1 Tf
-1.0137 -1.1116 TD
[(et)-308.8(al)20.7(.)]TJ
/F4 1 Tf
7.3823 0 0 6.5614 333.0708 280.1196 Tm
(10)Tj
9.843 0 0 9.843 343.4456 275.7543 Tm
[(Th)19.6(e)-313.3(s)0(t)15.1(u)0(d)20.8(y)-312.1(pr)20.9(ot)20.7(oc)13.9(ol)-301.8(wa)18.8(s)-311.9(a)0(p)19.7(p)0(r)20.9(o)0(v)15.1(e)0(d)-302.9(b)0(y)-301.7(t)0(h)20.7(e)-313.3(in)20.7(st)20.9(it)14.8(ut)20.7(io)20.7(na)19.7(l)]TJ
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T*
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0 -1.1116 TD
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T*
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(174)Tj
44.0011 0 TD
[(SENEVIRATNE)-338.8(ET)-338.7(AL.)]TJ
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T*
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T*
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/F9 1 Tf
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[(Measurement)-338.4(of)-330.4(RPV)-333.7(metabolites)]TJ
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[(Plasma,)-307.1(cervicovaginal)-309.6(uid,)-301.6(rectal)-309.8(uid,)-301.6(and)-304(vaginal)-304(tis-)]TJ
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[(olites)-463(by)-451.5(using)-460.5(an)-458.4(ultra-HPLC-tandem)-464.4(mass)-455.7(spectrometry)]TJ
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(9)Tj
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[(Briey,)-352(analytes)-346.4(of)-347.7(interest)]TJ
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[(were)-243.7(extracted)-245.2(by)-244.1(adding)-244(ice-cold)-242.9(acetonitrile)-243.1(conta)-8(ining)-236.2(the)]TJ
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[(internal)-483.8(standard)-477.6(\(IS\),)-479.9(RPV-d6)-480.6(at)-475.8(100)-170.3(ng/mL)-480.4(\(200)]TJ
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[(L)-267.2(for)-268.2(cervicovaginal)-275(uid)-269.3(and)-269.4(rectal)-269.5(uid\).)]TJ
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T*
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T*
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[(centrifuged)-332.6(for)-331.5(10)-169.2(min)-327.2(at)-331.8(10,000)]TJ
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13.5929 0 TD
(g)Tj
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[(at)-331.8(4)]TJ
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()Tj
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[(C.)-328.1(Supernatant)-332.5(was)]TJ
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[(collected)-510.3(and)-505.6(dried)-507.9(under)-502(vacuum.)-508.9(Samples)-506.4(were)-508.7(recon-)]TJ
T*
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[(L)-382.4(for)-377.6(plasma,)-382.2(100)]TJ
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[(L)-376.7(for)-383.4(cervi-)]TJ
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[(covaginal)-624.2(uid)-626.4(and)-620.8(rectal)-620.8(uid,)-624.1(and)-620.8(50)]TJ
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[(L)-618.6(for)-619.5(tissue\),)]TJ
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[(vortexed,)-296.9(and)-298.2(incubated)-295.9(at)-297.2(room)-293.6(temperature)-300.4(for)-291.2(10)-169.2(min)-292.6(be-)]TJ
T*
[(fore)-368.4(centrifugation)-370.7(for)-366.1(5)-162.4(min)-367.5(at)-366.4(10,000)]TJ
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(g)Tj
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1.5897 0 TD
()Tj
/F4 1 Tf
.3974 0 TD
[(C.)-362.7(Resulting)]TJ
-19.1683 -1.1174 TD
[(supernatant)-9.9(s)-375.3(were)-382(collected)-383.6(for)-377.6(mass)-380.8(spectral)-381(analyses,)-378.3(in-)]TJ
0 -1.1116 TD
[(jecting)-298.4(10)]TJ
/F10 1 Tf
4.2046 0 TD
(l)Tj
/F4 1 Tf
.5472 0 TD
[(L)-296(per)-292.4(sample)-298.1(from)-293.5(plasma,)-295.8(cervicovaginal)-298.1(uid,)]TJ
-4.7518 -1.1116 TD
[(and)-471(rectal)-471.1(uid)-465.1(and)-471(5)]TJ
/F10 1 Tf
9.5093 0 TD
(l)Tj
/F4 1 Tf
.5529 0 TD
[(L)-463.1(per)-471(sample)-470.9(from)-466.3(tissue.)-471.8(Liquid)]TJ
15.4475 67.9242 TD
[(chromatography-tandem)-469.3(mass)-461.4(spectrometry)-461.4(analy)-8(ses)-459.1(were)]TJ
0 -1.1174 TD
[(carried)-258.9(out)-256.9(by)-255.6(using)-253.1(a)-255.7(Dionex)-262.2(Ultimate)-255.7(3000)-257.8(uHPLC)-256.1(system)]TJ
0 -1.1116 TD
[(coupled)-407.6(to)-405.5(a)-405.4(TSQ)-402.6(Vantage)-409.6(Triple)-406.6(Stage)-411(Quadrupole)-406(mass)]TJ
T*
[(spectrometer)-284.1(\(Thermo)-281.9(Scientic\).)]TJ
1.0137 -1.1116 TD
[(In)-405.3(th)20.7(e)-417(s)0(e)19.9(l)0(e)19.6(c)0(t)19.5(e)0(d)-406.5(r)0(e)19.7(a)0(c)18.5(t)0(i)20.6(o)0(n)-405.4(m)0(o)19.6(n)0(i)14.9(t)0(o)20.7(r)0(i)20.7(n)0(g)-405.4(m)0(o)19.6(d)0(e)19.7(,)-418.1(fr)20.9(ag)19.7(me)18.4(nt)-405.5(io)20.7(ns)]TJ
-1.0137 -1.1174 TD
[(we)18.8(re)-550.5(de)19.7(te)19.6(ct)19.5(ed)-550.5(by)-549.4(po)20.8(si)20.9(ti)20.6(ve)-550.5(io)20.7(ni)15(za)18.5(ti)20.6(on)-549.4(us)21(in)20.7(g)-559.8(t)0(h)20.7(e)-561(fo)20.9(ll)20.6(ow)20(in)20.7(g)]TJ
0 -1.1116 TD
[(tr)20.7(an)19.7(si)20.9(ti)14.8(on)20.8(s)-352.2(\()0(Q)20(1)]TJ
/F11 1 Tf
6.3069 0 TD
(/)Tj
/F4 1 Tf
1.5494 0 TD
[(Q3)20(\):)-342.1(38)20.8(3)]TJ
/F11 1 Tf
3.7899 0 TD
(/)Tj
/F4 1 Tf
1.3535 0 TD
[(22)20.8(2)]TJ
/F5 1 Tf
1.8258 0 TD
[(m/)19.8(z)]TJ
/F4 1 Tf
1.7164 0 TD
[(\(m)19.6(on)20.8(oh)15.1(yd)20.8(ro)20.9(xy)20.8(la)19.5(te)19.5(d)]TJ
-16.5419 -1.1116 TD
[(RP)20(V\))20(,)-233.8(3)0(9)20.8(9)]TJ
/F11 1 Tf
4.3486 0 TD
(/)Tj
/F4 1 Tf
1.3535 0 TD
[(18)20.8(3)]TJ
/F5 1 Tf
1.7106 0 TD
[(m/)19.8(z)]TJ
/F4 1 Tf
1.5954 0 TD
[(\(d)15.1(ih)20.7(yd)20.8(ro)20.9(xy)20.8(la)13.8(te)19.6(d)-231.5(R)0(P)20(V)0(\))20(,)-233.8(39)20.8(9)]TJ
/F11 1 Tf
10.8513 0 TD
(/)Tj
/F4 1 Tf
1.3535 0 TD
[(19)20.8(6)]TJ
/F5 1 Tf
1.7106 0 TD
[(m/)19.8(z)]TJ
/F4 1 Tf
-22.9236 -1.1174 TD
[(\(d)20.9(ih)20.7(yd)20.8(ro)15.1(xy)20.8(la)19.5(te)19.6(d)-554(R)0(P)20(V)0(\))14.2(,)-550.6(54)15.1(3)]TJ
/F11 1 Tf
11.4964 0 TD
(/)Tj
/F4 1 Tf
1.3478 0 TD
[(36)15.1(7)]TJ
/F5 1 Tf
2.0389 0 TD
[(m/)19.8(z)]TJ
/F4 1 Tf
1.918 0 TD
[(\(R)19.8(PV)-550.1(gl)20.7(uc)19.7(ur)20.9(on)20.8(id)14.9(e)]TJ
-16.8011 -1.1116 TD
[(co)19.7(nj)20.7(ug)20.8(at)19.6(e\))14(,)-377.8(5)0(5)20.8(9)]TJ
/F11 1 Tf
6.4048 0 TD
(/)Tj
/F4 1 Tf
1.3535 0 TD
[(38)20.8(3)]TJ
/F5 1 Tf
1.8546 0 TD
[(m/)19.8(z)]TJ
/F4 1 Tf
1.7452 0 TD
[(\(m)19.6(on)20.8(oh)20.8(yd)20.8(ro)15.1(xy)20.8(la)19.6(te)19.5(d)-375.5(R)0(P)14.2(V)-376.4(gl)20.7(uc)19.7(u-)]TJ
-11.3581 -1.1116 TD
[(ro)20.9(ni)20.7(de)-763.6(co)19.7(nj)20.7(ug)15.1(at)19.5(e\))19.7(,)-769.5(a)0(n)19.7(d)-772.9(57)20.8(5)]TJ
/F11 1 Tf
12.2797 0 TD
(/)Tj
/F4 1 Tf
1.3535 0 TD
[(39)20.8(9)]TJ
/F5 1 Tf
2.252 0 TD
[(m/)19.8(z)]TJ
/F4 1 Tf
2.1368 0 TD
[(\(d)20.9(ih)15(yd)20.8(ro)20.9(xy)20.8(la)19.5(te)19.5(d)]TJ
-18.0221 -1.1174 TD
[(RP)20(V)-462.7(g)0(l)20.7(u)0(c)19.7(u)0(r)20.9(o)0(n)20.8(i)0(d)20.7(e)-463(co)19.7(nj)20.7(ug)15.1(at)19.5(e\))19.7(.)-458.4(T)0(h)19.6(e)-463(li)20.6(mi)19.5(t)-462(o)0(f)-451.4(q)0(u)20.8(a)0(n)19.7(t)0(i)20.6(t)0(a)19.6(t)0(i)20.6(o)0(n)-451.5(f)0(o)20.9(r)]TJ
0 -1.1116 TD
[(2-)20.9(hy)20.8(dr)20.9(ox)15.1(ym)19.6(et)19.5(hy)20.8(l-)20.7(RP)20(V)-347.5(i)0(n)-336.4(p)0(l)20.7(a)0(s)14.1(m)15(a)-347.8(s)0(a)14.1(m)15(pl)14.9(es)-337.2(wa)18.8(s)-346.5(0)0(.)24.3(7)0(8)15.1(1)-156.6(ng)20.8(/m)19.5(L.)]TJ
T*
[(Pe)19.8(ak)19.7(s)-415.6(d)0(e)19.7(t)0(e)19.6(c)0(t)19.5(e)0(d)-400.8(t)0(h)15(a)0(t)-400.9(f)0(e)19.7(l)0(l)-405.6(b)0(e)19.7(l)0(o)20.7(w)-410.9(th)15(e)-411.2(l)0(i)20.6(m)0(i)19.5(t)-410.2(of)-405.3(qu)20.8(an)19.7(ti)20.6(ta)13.8(ti)20.6(on)-399.6(ar)19.7(e)]TJ
T*
[(re)19.7(po)20.8(rt)20.7(ed)-164.6(as)-164.4(de)13.9(te)19.5(ct)19.5(ab)19.7(le)19.6(.)-176.2(T)0(h)19.6(e)-175(ra)19.7(ng)20.8(e)-175(f)0(o)20.9(r)-173.9(th)20.7(e)-175(q)0(u)20.8(a)0(n)13.9(t)0(i)20.6(t)0(a)19.6(t)0(i)20.6(o)0(n)-163.5(o)0(f)-163.4(p)0(l)20.7(a)0(s)14.1(m)0(a)]TJ
0 -1.1174 TD
[(2-)20.9(hy)20.8(dr)20.9(ox)15.1(ym)19.6(et)19.5(hy)20.8(l-)20.7(RP)20(V)-226.6(w)0(a)13(s)-225.5(0.)24.3(78)15.1(1)20.8(1,)18.5(60)20.8(0)-156.6(n)0(g)20.8(/)0(m)19.5(L)0(.)-218.8(T)0(h)19.6(e)-226.9(st)20.9(an)19.7(da)19.7(rd)]TJ
0 -1.1116 TD
[(cu)19.7(rv)20.9(es)-245.1(we)18.8(re)-245.2(ca)18.5(lc)19.5(ul)20.7(at)19.5(ed)-245.3(by)-244.1(us)21(in)20.7(g)-254.5(G)0(r)20(a)0(p)19.7(h)0(P)15.2(a)0(d)-239.5(P)0(r)15.3(i)0(s)20.9(m)-250(\(S)15.3(an)-239.5(Di)14.1(eg)19.7(o,)]TJ
T*
[(CA)18.9(\))-237.2(b)0(y)-226.8(t)0(a)19.6(k)0(i)20.7(n)0(g)-226.8(t)0(h)20.7(e)-238.4(ra)19.7(ti)14.8(o)-237.2(o)0(f)-226.8(a)0(n)19.7(a)0(l)19.6(y)0(t)20.7(e)-238.4(pe)19.7(ak)-228(ar)19.7(ea)-229.2(ov)20.8(er)-228(IS)-226.6(an)19.7(d)-237.2()0(t)-226.8(b)0(y)]TJ
0 -1.1174 TD
[(us)21(in)20.7(g)-312.1(a)-313.3(we)18.8(ig)20.7(ht)20.7(ed)-302.9(\(1)20.9(/y)]TJ
7.3823 0 0 6.5614 396.3401 532.2329 Tm
(2)Tj
9.843 0 0 9.843 399.9684 527.8676 Tm
-.0203 Tc
[(\))-332.4(l)-20.3(in)-20.3(ea)-20.3(r)-323.1(r)-20.3(eg)-20.3(re)-20.3(s)-6.2(s)-20.3(io)-20.3(n,)-329(a)-20.3(n)-6.4(d)-326.7(c)-20.3(on)-20.3(c)-6.4(e)-20.3(nt)-20.3(ra)-20.3(ti)-20.3(on)-20.3(s)]TJ
-9.0543 -1.1116 TD
0 Tc
[(of)-261.4(sa)19.9(mp)19.6(le)19.5(s)-271.6(w)0(e)18.8(r)0(e)-262.5(i)0(n)20.7(t)0(e)19.5(r)0(p)20.9(o)0(l)14.9(a)0(t)19.5(e)0(d)-256.8(b)0(y)-261.4(u)0(s)21(i)0(n)14.9(g)-266(th)15(e)-267.2(c)0(u)19.7(r)0(v)15.1(e)0(s)19.9(.)]TJ
/F9 1 Tf
8.9663 0 0 8.9663 310.8472 494.9857 Tm
[(Statistical)-336.1(analysis)]TJ
/F4 1 Tf
9.843 0 0 9.843 320.8251 478.5447 Tm
[(Statistical)-436.5(analy)-8(ses)-436.1(were)-439.6(performed)-439.6(by)-439.9(using)-437.4(GraphPad)]TJ
-1.0137 -1.1116 TD
[(Prism)-403.9(\(San)-402.8(Diego,)-408.5(CA\).)-400.3(KruskalWallis)-412.6(tests)-404(followed)-408.5(by)]TJ
0 -1.1174 TD
[(Dunns)-220.4(test)-224.5(were)-226.4(performed,)-229.9(and)-223.3(signicance)-224(was)-224(denoted)-229(as)]TJ
0 -1.1116 TD
[(follows:)-297.8(*)]TJ
/F5 1 Tf
4.0779 0 TD
(p)Tj
/F7 1 Tf
.6624 0 TD
()Tj
/F4 1 Tf
.72 0 TD
[(.05;)-294.9(**)]TJ
/F5 1 Tf
2.828 0 TD
(p)Tj
/F7 1 Tf
.6681 0 TD
()Tj
/F4 1 Tf
.7142 0 TD
[(.01;)-294.8(***)]TJ
/F5 1 Tf
3.3291 0 TD
(p)Tj
/F7 1 Tf
.6681 0 TD
()Tj
/F4 1 Tf
.7142 0 TD
[(.001.)-298.2(The)-293.7(condence)-302.4(in-)]TJ
-14.382 -1.1116 TD
[(terval)-279.9(used)-281.8(was)-281.6(95%.)]TJ
/F9 1 Tf
8.9663 0 0 8.9663 310.8472 412.781 Tm
[(Genomic)-330.6(DNA)-338.6(isolation)-334.1(and)-335.7(sample)-333.8(preparation)]TJ
0 -1.2203 TD
[(for)-332.5(next-generation)-332.1(sequencing)]TJ
/F4 1 Tf
9.843 0 0 9.843 320.8251 385.3983 Tm
[(Genomic)-306(DNA)-305.4(was)-304.6(isolated)-305.1(from)-305.1(200)]TJ
/F10 1 Tf
15.6376 0 TD
(l)Tj
/F4 1 Tf
.5529 0 TD
[(L)-301.8(o)0(f)-307.4(whole)-301.4(blood)]TJ
-17.2042 -1.1174 TD
[(by)-244.1(using)-247.3(the)-246.5(QIAamp)-246.9(96)-244.1(DNA)-247.8(Blood)-248.6(Kit)-246.3(\(Qiagen,)-244.8(Valencia,)]TJ
0 -1.1116 TD
[(CA\))-408.4(according)-405.2(to)-411.3(the)-402(manufacturers)-412.8(instructions.)-409.6(Puried)]TJ
T*
[(DNA)-282.4(was)-281.6(eluted)-279.9(by)-284.4(using)-281.9(200)]TJ
/F10 1 Tf
12.4006 0 TD
(l)Tj
/F4 1 Tf
.5529 0 TD
[(L)-278.8(o)0(f)-278.6(elution)-285.7(buffer.)]TJ
-11.9399 -1.1174 TD
[(Samples)-575.5(were)-577.8(prepared)-582.4(following)-575.6(the)-580.6(TruSeq)-573.2(custom)]TJ
-1.0137 -1.1116 TD
[(amplicon)-260.3(library)-262.5(preparation)-263.5(kit)-262.8(guide)-260.2(\(Illumina,)-263.7(San)-263.5(Diego,)]TJ
T*
[(CA\))-333.5(by)-336.3(using)-333.7(250)-170.3(ng)-330.5(of)-336.2(template)-336.5(DNA)-340(per)-332.7(reaction.)-338.5(Agen-)]TJ
T*
[(court)-277.5(AMPure)-280.1(XP)-273.6(beads)-278.3(\(Beckman)-279.5(Coulter,)-278.5(Inc.,)-276.2(Brea,)-281.9(CA\))]TJ
0 -1.1174 TD
[(were)-318.6(used)-316.4(for)-314.3(PCR)-322(clean-up.)-315.3(The)-316.7(nal)-316.6(pooled)-318.9(DNA)-316.9(library)]TJ
0 -1.1116 TD
(\(6)Tj
/F10 1 Tf
.9964 0 TD
(l)Tj
/F4 1 Tf
.5529 0 TD
[(L\))-239.5(was)-241.3(diluted)-239.6(in)-238.5(594)]TJ
/F10 1 Tf
8.6914 0 TD
(l)Tj
/F4 1 Tf
.5529 0 TD
[(L)-238.4(HT1)-235.8(buffer)-238.1(and)-240.6(spiked)-238.1(with)-241.7(1%)]TJ
-10.7937 -1.1116 TD
[(PhiX.)-285.1(One)-287.6(technical)-291.4(control)-285.6(was)-287.4(included)-287.9(per)-286.7(sample)-286.6(batch,)]TJ
0 -1.1174 TD
[(and)-401.9(runs)-407.4(were)-410.7(sequenced)-406(by)-405.4(using)-408.6(an)-406.5(Illumina)-403.2(MiSeq)-410.7(se-)]TJ
0 -1.1116 TD
[(quencing)-282(platform)-282.1(generating)-285.4(150)-279.8(base)-283(pair)-282.1(reads.)]TJ
/F9 1 Tf
8.9663 0 0 8.9663 310.8472 231.9306 Tm
[(Next-generation)-336.8(sequencing)-330.4(targeted)]TJ
0 -1.2203 TD
[(enrichment)-335.7(design)]TJ
/F4 1 Tf
9.843 0 0 9.843 320.8251 204.548 Tm
.012 Tc
[(S)5.3(e)-1.8(q)5.1(u)-.6(encin)5.1(g)-236.8(was)-236.6(p)5.1(er)5.2(fo)5.1(rmed)-236.8(by)-236.8(u)5.1(s)-.4(i)5(n)-.6(g)-236.8(t)5(he)-237.9(Il)5(lu)5.1(mi)5(na)-237.9(Tru)5.1(S)-.4(eq)]TJ
-1.0137 -1.1174 TD
.0117 Tc
[(cust)4.7(om)-261.3(amp)4.8(l)-1(i)4.7(c)-2.1(o)4.8(n)-260.1(v1.5)-260.1(k)4.8(it)-260.2(\(S)5(an)-260.1(Dieg)4.8(o,)-256.7(CA\).)-262.4(Cus)5(t)-1(om)-261.3(p)4.8(r)-.9(o)4.8(b)-.9(es)]TJ
0 -1.1116 TD
.0071 Tc
[(ta)-6.7(rg)-5.5(e)-6.7(t).1(i)-5.6(n).2(g)-189.8(t)-5.6(he)-191(e)-6.7(x).2(o)-5.5(n)-5.5(i).1(c)-191(r)-5.5(eg)-5.5(io)-5.5(ns)-195.4(of)]TJ
/F5 1 Tf
12.464 0 TD
.0137 Tc
[(CY)7(P3)6.8(A4)]TJ
/F4 1 Tf
3.5077 0 TD
0 Tc
(,)Tj
/F5 1 Tf
.4493 0 TD
.0095 Tc
(CYP3A5)Tj
/F4 1 Tf
3.5077 0 TD
0 Tc
(,)Tj
/F5 1 Tf
.4493 0 TD
.0085 Tc
[(UG)-5(T1A1)]TJ
/F4 1 Tf
3.6632 0 TD
0 Tc
(,)Tj
-24.041 -1.1116 TD
.0103 Tc
(and)Tj
/F5 1 Tf
1.9007 0 TD
.0131 Tc
[(UGT)6.4(1A)5(4)]TJ
/F4 1 Tf
4.0952 0 TD
.0104 Tc
[(wer)3.6(e)-429.6(g)3.5(e)-3.4(nerated)]TJ
/F5 1 Tf
6.8368 0 TD
.007 Tc
[(in)-431.8(s)-5.4(i)0(l)-5.7(i)0(c)-6.8(o)]TJ
/F4 1 Tf
3.8936 0 TD
.0069 Tc
[(by)-431.9(us)-5.5(in)-5.7(g)-431.9(I).1(l)-5.8(l)-.1(u)-5.7(m)-1.2(i)-5.8(n)-5.7(a)]TJ
-16.7262 -1.1116 TD
.0119 Tc
[(Des)5.2(i)-.8(gn)5(St)4.9(ud)5(io)-231.1(sof)5.1(t)-.8(war)5.1(e)-1.9(.)-233.4(T)3.9(he)-232.3(ch)5(ro)5(mo)5(somal)-237(c)3.9(oo)5(rdi)4.9(nates)-236.7(u)5(sed)]TJ
0 -1.1174 TD
.0115 Tc
[(wer)4.7(e)-1010.2(as)-1003.1(fol)4.5(lo)4.6(ws:)]TJ
/F5 1 Tf
9.2213 0 TD
.0095 Tc
(CYP3A4)Tj
/F4 1 Tf
4.5156 0 TD
.0069 Tc
[(7:)-5.8(99)-5.7(35)-5.7(4)-5.7(5)0(8)-5.7(3)0()-5.7(7)0(:)-5.8(9)-5.7(93)-5.7(81)-5.7(81)-5.7(1;)]TJ
/F5 1 Tf
-13.7369 -1.1116 TD
.0095 Tc
(CYP3A5)Tj
/F4 1 Tf
3.7265 0 TD
.0126 Tc
[(7:)5.6(99)5.7(245)5.7(81)5.7(3)5.7(7:)5.6(992)5.7(77)5.7(62)5.7(1;)]TJ
/F5 1 Tf
10.7879 0 TD
.0085 Tc
[(UG)-5(T1A1)]TJ
/F4 1 Tf
3.882 0 TD
.0126 Tc
[(2:)5.6(234)5.7(66)5.7(89)5.7(19)5.7()]TJ
-18.3965 -1.1116 TD
[(2)5.7(:)-.1(2)5.7(346)5.7(81)5.7(94)5.7(5;)]TJ
/F5 1 Tf
6.2838 0 TD
.0133 Tc
[(UG)5.6(T1)6.4(A4)]TJ
/F4 1 Tf
4.2679 0 TD
.0127 Tc
[(2)5.8(:)0(23)5.8(46)5.8(27)5.8(43)5.8(82)5.8(:2)5.8(34)5.8(681)5.8(94)5.8(5.)-595.5(Th)5.8(e)]TJ
-10.5518 -1.1174 TD
.0072 Tc
[(n)-5.4(al)-287.8(de)-6.6(si)-5.5(g)-5.4(n)-281.9(in)-5.4(cl)-5.5(ud)-5.4(e)-6.6(d)-281.9(12)-5.4(0)-281.9(a)-6.6(mpl)-5.5(i)-5.5(c)-.8(o)-5.4(n).3(s)-5.2(.)]TJ
/F9 1 Tf
8.9663 0 0 8.9663 310.8472 94.9039 Tm
0 Tc
[(Next-generation)-336.8(sequencing)-330.4(data)-332.9(analysis)]TJ
/F4 1 Tf
9.843 0 0 9.843 320.8251 78.463 Tm
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[(tandem)-245.7(mass)-242.1(spectrometry)-241.3(assay,)-246.4(as)-239.1(previously)-247.3(published.)]TJ
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(9)Tj
9.845 0 0 9.845 297.1842 96.4913 Tm
[(The)-241.4(2-hydroxymethyl-RPV)-241.9(metabolite)-245.6(was)-240.9(quantied)-247.5(by)-238.1(using)-241.1(a)]TJ
-23.8864 -1.0077 TD
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T*
[(collected)-365.4(from)-362.2(study)-362(sites,)-360.8(Bronx/Newark,)-365.9(USA)]TJ
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[(23,)-362.4(Cape)-364.3(Town,)-360.6(South)-362(Africa)]TJ
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[(25,)-356.6(Harare,)-364.9(Zimbabwe)]TJ
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[(35)-364.8(were)]TJ
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[(.01;)-334.8(***)]TJ
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[(.001.)-332.2(IS,)-333.4(internal)-339(standard;)-333.9(RPV,)-336.2(rilpivirine.)]TJ
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(176)Tj
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