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[(acid)6.3(s)-298.7(\()6.4(D)-.3(iHET)5.2(rEs)-293(o).6(r)-293.1(DHET)5.2(s).8(\).)-295.5(T)5.2(h).6(ese)-294.3(p).6(ath)6.3(w)-.3(ays)-293(for)-293.1(AA)-294(m)5.1(e)-.6(tab-)]TJ
0 -1.1116 TD
-.0166 Tc
[(olism)-278.1(a)-1.6(re)-278(summarized)-282.6(in)-276.9(Figu)5.3(re)-283.8(1A.)]TJ
1.0137 -1.1116 TD
0 Tc
[(AA)-297.7(is)-290.1(th)15(e)-301.8(m)0(a)18.4(i)0(n)-296.1(s)0(u)21(b)0(s)21(t)0(r)15(a)0(t)19.6(e)-301.8(fo)15.1(r)-300.6(C)0(O)18.9(X)0(,)-299.2(L)0(O)18.8(X)0(,)-293.4(a)0(n)19.7(d)-306.4(CY)18.9(P)-306.2(a)0(n)19.7(d)-306.4(is)]TJ
-1.0137 -1.1174 TD
[(pr)20.9(im)19.5(ar)19.7(il)14.8(y)-398.5(r)0(e)19.7(l)0(e)19.6(a)0(s)14.1(e)0(d)-389.3(b)0(y)-393.9(o)0(n)20.8(e)-399.7(is)15.1(of)20.9(or)20.9(m)-399.7(o)0(f)-393.8(t)0(h)20.7(e)-405.4(ph)20.8(os)21(ph)20.8(ol)20.7(ip)15(as)19.9(e)-399.7(A)]TJ
7.3823 0 0 6.5614 297.4109 252.17 Tm
(2)Tj
9.843 0 0 9.843 62.022 242.8724 Tm
[(su)21(pe)19.7(rf)15.1(am)18.5(il)20.6(y)-300.6(\()0(P)21(L)0(A)]TJ
7.3823 0 0 6.5614 132.6047 241.2283 Tm
(2)Tj
9.843 0 0 9.843 136.1763 242.8724 Tm
[(\),)-292.5(na)19.7(me)18.4(ly)-290.3(cy)19.7(to)20.7(so)21(li)20.6(c)-301.8(P)0(L)19.8(A)]TJ
7.3823 0 0 6.5614 232.4409 241.2283 Tm
(2)Tj
/F10 1 Tf
9.843 0 0 9.843 236.0692 242.8724 Tm
(a)Tj
/F5 1 Tf
.8006 0 TD
[(gr)20.9(ou)20.8(p)-300.6(I)0(V)-291(\()0(1)20.9(3)0(\))20.9(.)]TJ
-18.4829 -1.1116 TD
[(Th)19.6(is)-186.4(en)19.7(zy)13.9(m)15(e)-203.8(ha)19.7(s)-196.7(a)0(n)-187.7(N)0(-)20(t)0(e)19.6(r)0(m)19.6(i)0(n)20.7(a)0(l)-193.6(C)0(a)]TJ
/F9 1 Tf
7.3823 0 0 6.5614 194.6834 236.296 Tm
(++)Tj
/F5 1 Tf
9.843 0 0 9.843 202.6204 231.9306 Tm
[(-d)20.9(ep)19.7(en)19.7(de)13.9(nt)-186.6(ph)20.8(os)21(ph)20.8(ol)20.7(ip)15(id)20.7(-)]TJ
-14.2841 -1.1174 TD
[(bi)20.7(nd)20.8(in)15(g)-220(d)0(o)15.1(m)15(ai)13.8(n,)-211.9(wh)20(ic)19.5(h)-225.7(u)0(n)20.8(d)0(e)19.7(r)-225.7(Ca)]TJ
/F9 1 Tf
7.3823 0 0 6.5614 188.4472 225.3543 Tm
(++)Tj
/F5 1 Tf
9.843 0 0 9.843 196.4409 220.9322 Tm
[(-)-225.7(s)0(t)20.9(i)0(m)19.5(u)0(l)20.7(i)-225.9(le)19.6(ad)19.7(s)-225.5(t)0(o)-215.4(a)0(c)18.5(t)0(i)20.6(v)0(a)13.9(t)0(i)20.6(o)0(n)]TJ
-13.6563 -1.1116 TD
[(an)19.7(d)-346.7(t)0(r)20.7(a)0(n)19.7(s)0(l)20.9(o)0(c)19.7(a)0(t)13.8(i)0(o)20.7(n)-340.9(of)-336.2(cy)19.7(to)20.7(so)21(li)14.8(c)-342.1(p)0(h)20.8(o)0(p)20.8(h)0(o)15.1(l)0(i)20.6(p)0(a)19.7(s)0(e)-337.2(A)0(2)-331.4(\()0(c)19.7(P)0(L)19.8(A)]TJ
7.3823 0 0 6.5614 278.4188 208.3464 Tm
(2)Tj
9.843 0 0 9.843 282.0472 209.9905 Tm
(\))Tj
/F10 1 Tf
.3225 0 TD
(a)Tj
/F5 1 Tf
.8467 0 TD
(to)Tj
-23.5226 -1.1116 TD
[(th)20.7(e)-365.1(e)0(n)13.9(d)0(o)20.8(p)0(l)20.7(a)0(s)19.9(m)0(i)19.5(c)-365.1(re)19.7(ti)14.8(cu)19.7(lu)20.7(m)-365.2(a)0(n)19.7(d)-364(pe)19.7(ri)20.7(nu)15.1(cl)19.5(ea)18.5(r)-363.9(m)0(e)18.4(m)0(b)19.6(r)0(a)19.7(n)0(e)19.7(s)-369.5(wi)19.8(th)]TJ
0 -1.1174 TD
[(si)20.9(mu)19.6(lt)20.6(an)13.9(eo)19.7(us)-387.9(ph)20.8(os)21(ph)15.1(or)20.9(yl)20.7(at)19.5(io)20.7(n)-398.5(o)0(f)-393.8(t)0(h)20.7(e)-399.7(pr)20.9(ot)20.7(ei)19.5(n)-398.5(\()0(5)15.1(0)0(,)-384.7(9)0(9)15.1(\))0(.)-390.4(M)15.3(os)15.3(t)]TJ
0 -1.1116 TD
[(ce)18.5(ll)20.6(s)-519.3(a)0(n)13.9(d)-519.5(ti)20.6(ss)21.2(ue)19.7(s)-519.3(c)0(o)19.7(n)0(s)15.3(t)0(i)20.6(t)0(u)20.7(t)0(i)20.6(v)0(e)19.7(l)0(y)-509.2(e)0(x)19.7(p)0(r)15.1(e)0(s)19.9(s)-519.3(cP)19.8(LA)]TJ
7.3823 0 0 6.5614 249.1086 175.4645 Tm
(2)Tj
/F10 1 Tf
9.843 0 0 9.843 252.7369 177.1086 Tm
(a)Tj
/F5 1 Tf
.4896 0 TD
.5196 Tc
[(;h)519.6(o)540.4(w)519.6(e)538.4(v)519.6(e)539.3(r)519.6(,)]TJ
-19.8652 -1.1116 TD
0 Tc
[(ce)18.5(rt)20.7(ai)19.5(n)-444.6(p)0(r)20.9(o)0(i)20.7(n)0()15.2(a)0(m)24.2(m)0(a)18.4(t)0(o)15(r)0(y)-428.4(c)0(y)19.7(t)0(o)20.7(k)0(i)14.9(n)0(e)19.7(s)-438.6(an)19.7(d)-444.6(g)0(r)20.9(o)0(w)20(t)0(h)-434.3(f)0(a)19.7(c)0(t)19.5(o)0(r)20.9(s)-444.4(ma)18.4(y)]TJ
T*
[(co)19.7(nt)20.7(ri)15(bu)20.8(te)-268.4(to)-267.3(in)20.7(cr)14(ea)18.5(se)19.9(d)-277.6(c)0(P)19.8(L)0(A)]TJ
7.3823 0 0 6.5614 176.1448 153.5811 Tm
(2)Tj
/F10 1 Tf
9.843 0 0 9.843 179.7732 155.2252 Tm
(a)Tj
/F5 1 Tf
.7776 0 TD
[(ex)19.7(pr)20.9(es)19.9(si)15.1(on)-267.1(\(5)20.9(2\))20.9(.)-279.9(I)0(n)-267.1(i)0(s)15.1(c)0(h)19.7(e)0(m)18.5(i)0(a)19.5(-)]TJ
-12.7405 -1.1174 TD
[(an)19.7(d)-525.2(i)0(n)20.7()0(a)19.8(m)0(m)18.4(a)0(t)19.5(i)0(o)20.7(n)0(-)15.1(r)0(e)19.7(l)0(a)19.5(t)0(e)19.6(d)-525.2(di)20.7(se)19.9(as)19.9(es)14.1(,)-521.8(i)0(n)20.7()0(a)19.8(m)0(m)18.4(a)0(t)19.5(o)0(r)20.9(y)-525.2(cy)19.7(to)20.7(ki)14.9(ne)19.7(s)]TJ
0 -1.1116 TD
[(an)19.7(d)-335.2(R)0(O)18.9(S)-335(in)20.7(cr)19.7(ea)18.5(se)-325.7(th)20.7(e)-336.3(a)0(c)18.5(t)0(i)20.6(v)0(i)20.7(t)0(y)-324.9(o)0(f)-324.7(c)0(P)19.8(L)0(A)]TJ
7.3823 0 0 6.5614 217.9842 131.6409 Tm
(2)Tj
9.843 0 0 9.843 221.6125 133.285 Tm
.3317 Tc
[(,t)331.7(h)352.4(u)331.7(s)7.2(a)331.7(l)351.2(l)331.7(o)346.7(w)331.7(i)351.5(n)331.7(g)7(a)331.7(u)351.4(g)331.7(-)]TJ
-16.2136 -1.1116 TD
0 Tc
[(me)18.4(nt)20.7(ed)-210.7(re)14(le)19.6(as)19.9(e)-221.1(o)0(f)-209.5(A)0(A)-211.3(f)0(r)15.1(o)0(m)-210.8(m)0(e)18.4(m)0(b)19.6(r)0(a)19.7(n)0(e)19.7(s)-219.8(\(8)20.9(5\))15.1(.)-216.5(M)0(e)18.8(c)0(h)19.7(a)0(n)13.9(i)0(s)20.9(t)0(i)20.6(c)0(a)18.5(l)0(l)20.6(y)0(,)]TJ
0 -1.1174 TD
[(it)-278.9(ha)19.7(s)-288.9(b)0(e)19.7(e)0(n)-279.8(d)0(e)19.7(s)0(c)19.9(r)0(i)15(b)0(e)19.7(d)-289.1(th)20.7(at)-280(in)20.7(cr)19.7(ea)18.5(se)19.9(d)-289.1(n)0(i)20.7(c)0(o)19.7(t)0(i)20.6(n)0(a)13.9(m)15(id)15(e)-284.5(a)0(d)19.7(e)0(n)13.9(i)0(n)20.7(e)-290.2(di)20.7(-)]TJ
0 -1.1116 TD
[(nu)20.8(cl)19.5(eo)19.7(ti)14.8(de)-550.5(ph)20.8(os)21(ph)20.8(at)19.5(e,)-552.9(NA)19.1(DP)20.1(H,)-546.8(ox)15.1(id)20.7(as)19.9(e)-560.9(a)0(c)18.5(t)0(i)20.6(v)0(i)20.7(t)0(y)-549.5(i)0(n)20.7(c)0(r)19.7(e)0(a)18.5(s)0(e)14.1(s)]TJ
T*
[(RO)18.9(S)-265.9(l)0(e)19.6(v)0(e)19.7(l)0(s)20.9(,)-262.6(in)20.7(ac)18.5(ti)20.6(va)19.7(ti)14.8(ng)-249.9(pr)20.9(ot)20.7(ei)13.8(n)-260.3(p)0(h)20.8(o)0(s)21(p)0(h)20.8(a)0(t)13.8(a)0(s)19.9(e)0(s)-250.8(s)0(u)21(c)0(h)-256.8(a)0(s)-250.8(p)0(r)15.1(o)0(t)20.7(e)0(i)19.6(n)]TJ
0 -1.1174 TD
[(ty)20.7(ro)20.9(si)15.1(ne)-913.4(ph)20.8(os)15.3(ph)20.8(at)19.5(as)19.9(e,)-915.7(mi)19.5(to)20.7(ge)19.7(n-)15.1(ac)18.5(ti)20.6(va)19.7(te)19.6(d)-922.6(p)0(r)15.1(o)0(t)20.7(e)0(i)19.6(n)-922.6(ki)14.9(na)19.7(se)]TJ
0 -1.1116 TD
[(\(M)20(AP)20.1(K\))-262.2(ph)20.8(os)21(ph)20.8(at)19.5(as)14.1(e)-267.2(1)0(,)-258(a)0(s)-256.6(w)0(e)13(l)0(l)-255.9(a)0(s)-256.6(p)0(r)15.1(o)0(t)20.7(e)0(i)19.5(n)-266(ph)20.8(os)15.3(ph)20.8(at)19.6(as)19.9(e)-267.2(1)-271.8(an)19.7(d)]TJ
T*
[(2A)-227.7(\(P)21(P1)-226.7(an)19.7(d)-237.2(P)0(P)15.4(2)0(A)20(,)-233.8(re)19.7(sp)21(ec)12.8(ti)20.6(ve)19.7(ly)20.7(\).)-229.1(Th)19.6(is)-226.8(re)19.7(su)21(lt)20.6(s)-237(i)0(n)-227(a)0(c)18.5(t)0(i)20.6(v)0(a)13.9(t)0(i)20.6(o)0(n)-226.8(o)0(f)]TJ
25.504 67.9242 TD
[(MA)13.3(PK)-221.8(ca)12.8(sc)19.9(ad)19.7(es)-227.8(su)21(ch)-228(as)-227.8(c-)19.7(Ju)21(n)-237.2(N)0(-)20(t)0(e)19.6(r)0(m)19.6(i)0(n)14.9(a)0(l)-228.1(k)0(i)20.7(n)0(a)19.7(s)0(e)-227.8(\()-116.3(JN)20.2(K\))20(,)-233.8(p)0(3)15.1(8)0(,)]TJ
0 -1.1174 TD
[(an)13.9(d)-651.9(e)0(x)19.7(t)0(r)20.7(a)0(c)18.5(e)0(l)13.8(l)0(u)20.7(l)0(a)19.6(r)-651.9(si)15.1(gn)20.8(al)19.5(-r)20.9(eg)19.7(ul)20.7(at)19.5(ed)-648.4(ki)20.7(na)19.7(se)19.9(,)-660(r)0(e)19.7(s)0(p)21(o)0(n)20.8(s)0(i)20.9(b)0(l)20.7(e)-658.9(fo)20.9(r)]TJ
0 -1.1116 TD
[(cP)14.1(LA)]TJ
7.3823 0 0 6.5614 335.6786 701.5746 Tm
(2)Tj
/F10 1 Tf
9.843 0 0 9.843 339.2503 703.2188 Tm
(a)Tj
/F5 1 Tf
.7718 0 TD
[(ac)18.5(ti)20.6(va)19.7(ti)20.6(on)-261.4(\(8)20.9(5\))20.9(.)]TJ
/F3 1 Tf
8.9663 0 0 8.9663 313.0582 681.2786 Tm
[(Biosynthesis)-341.9(of)-330.2(PGs)-334.2(and)-331.9(TXs)]TJ
/F5 1 Tf
9.843 0 0 9.843 323.0361 664.8376 Tm
-.0157 Tc
[(The)-363.5(m)-.7(a)5.1(j)-15.7(o)10.8(r).5(ity)-356.6(o).5(f)-362.3(our)-362.3(cells)-356.4(synthes)-15.7(i)11(ze)-357.8(PGs,)-359(which)-362.4(act)-362.5(in)-356.6(an)]TJ
-1.0137 -1.1116 TD
[(auto)-15.8(c)15.4(r)-15.8(i)10.7(n).4(e)-277.2(a)-.8(nd)-276.1(paracrine)-277.2(manner.)-278.4(PGs)-275.9(a)-.8(re)-277.2(synthesized)]TJ
/F6 1 Tf
20.9653 0 TD
-.016 Tc
[(de)-283.2(novo)]TJ
/F5 1 Tf
3.0814 0 TD
0 Tc
(,)Tj
-24.0468 -1.1174 TD
-.0158 Tc
[(i)-15.8(n)-357.9(respons)-15.8(e)-358.8(t).2(o)-374(mechanical)-368.4(injur)-15.8(y)-357.8(or)-374(by)-374(specic)-375.2(stimuli)-368.4(\()]TJ
/F6 1 Tf
22.6587 0 TD
-.0145 Tc
(e.g)Tj
/F5 1 Tf
1.1519 0 TD
-.0139 Tc
(.,)Tj
-23.8106 -1.1116 TD
-.016 Tc
[(cyto)-16(k)10.6(i).1(nes)-425.8(a)-1(nd)-431.8(growth)-431.8(factors\))-431.8(\(149\).)-428.4(AA)-432.7(is)-431.6(metaboli)-16(z)15.1(ed)-431.8(by)]TJ
T*
[(COX,)-226.7(also)-224.3(k)-15.9(n)10.7(own)-224.3(a)-.9(s)-224.2(prostaglandin)-224.3(H)-231(\(PGH\))-224.3(synthase)-225.5(\(PGHS)-15.9(\))10.9(,)]TJ
0 -1.1174 TD
-.0158 Tc
[(t)-15.8(o)-311.9(an)-327.9(intermediate)-323.3(endoperoxide,)-324.5(P)-15.8(G)10.1(H)]TJ
7.3823 0 0 6.5614 463.181 608.3715 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 466.6959 610.0156 Tm
-.0156 Tc
[(,)-324.3(w)-.3(hich)-327.7(is)-321.8(f)-15.6(u)11(rther)-321.9(me-)]TJ
-15.6088 -1.1116 TD
-.0158 Tc
[(t)-15.8(a)15.3(bo)-15.8(l)10.7(i).3(zed)-374(into)-379.8(PGE)]TJ
7.3823 0 0 6.5614 388.233 597.4297 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 391.7479 599.0739 Tm
.3605 Tc
[(,P)360.5(G)386.4(D)]TJ
7.3823 0 0 6.5614 416.9196 597.4297 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 420.4345 599.0739 Tm
.3605 Tc
[(,P)376.8(G)375.8(F)]TJ
7.3823 0 0 6.5614 443.9054 597.4297 Tm
0 Tc
(2)Tj
/F10 1 Tf
.4838 0 TD
(a)Tj
/F5 1 Tf
9.843 0 0 9.843 450.992 599.0739 Tm
-.0158 Tc
[(,)-376.3(pros)-15.8(t)10.9(acyclin)-374(\(PGI)]TJ
7.3823 0 0 6.5614 525.5432 597.4297 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 529.1148 599.0739 Tm
-.0159 Tc
[(\),)-376.4(and)]TJ
-21.9502 -1.1116 TD
-.0152 Tc
(TXA)Tj
7.3823 0 0 6.5614 332.7873 586.488 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 340.1007 588.1321 Tm
-.016 Tc
[(\(67,)-376.5(149\).)-382.3(The)-381.1().3(rst)-380.1(phase)-381.1(of)-379.9(the)-375.4(C)-.8(OX)-380.8(reaction)-380(i)0(s)-379.8(a)-1(b-)]TJ
-2.7474 -1.1174 TD
[(s)-15.9(t)10.8(raction)-201.3(o).3(f)-201.3(t)-15.9(h)10.6(e)-202.5(13-pro)-201.3(S)-206.9(hydrogen)-201.3(from)-208.3(AA)-202.2(by)-201.3(a)-208.2(t).2(yrosyl)-201.4(radical)]TJ
0 -1.1116 TD
-.0158 Tc
[(\()-15.8(T)15.4(yr)-15.8(3)10.8(85\))-201.2(to)-201.2(form)-202.4(an)-201.2(arachidonyl)-207.1(radical,)-197.8(w)-.5(hich)-207(then)-201.2(reacts)-201(w)-.5(ith)]TJ
T*
0 Tc
(O)Tj
7.3823 0 0 6.5614 319.9747 553.6061 Tm
(2)Tj
9.843 0 0 9.843 326.381 555.2502 Tm
-.0158 Tc
[(in)-293.4(a)-288.8(r).4(egio-)-293.3(a)-.8(nd)-287.6(stereos)-15.8(e)15.6(l)-15.8(e)15.3(cti)-15.8(v)10.7(e)-288.8(manner)-287.6(\().4(Fig.)-289.9(2A\))-15.8(.)-279.5(After)-287.6(a)-.8(n-)]TJ
-1.3535 -1.1116 TD
-.0159 Tc
[(t)-15.9(a)15.2(r)-15.9(a)9.6(facial)-639.2(oxygen)-639(i).2(nsertion)-644.8(a)-.9(t)-639.2(C)-.7(-11,)-641.4(the)-640.2(r).3(es)-15.9(u)10.9(l).2(ting)-639(11\(R\)-)]TJ
0 -1.1174 TD
-.0158 Tc
[(hy)-15.8(d)10.8(roperoxyl)-230.1(radical)-230.1(reacts)-229.8(a)-.8(t)-230.1(C)-.6(-9)-230(to)-230(generate)-231.2(an)-230(endoperoxide)]TJ
0 -1.1116 TD
[(gr)-15.8(o)10.8(u).4(p)-374(a)-.8(nd)-374(a)-375.2(C)-.6(-8)-374(radical.)-376.3(T)-.8(hen,)-376.3(C-8)-374(a)-.8(nd)-374(C-12)-374(are)-375.2(c)-.8(onnected)]TJ
T*
[(t)-15.8(h)10.7(rough)-195.4(cyclization)-195.4(t).3(o)-195.4(form)-196.7(a)-190.8().5(ve-)-15.8(m)15.4(embered)-195.4(ring)-195.4(and)-195.5(a)-196.6(carbon-)]TJ
0 -1.1174 TD
[(center)-15.8(e)15.4(d)-224.2(r).4(adical)-218.6(on)-218.5(C-15.)-215.1(In)-224.2(the)-219.6().5(nal)-218.6(s).6(tep,)-215.1(a)-219.6(s)-15.8(e)9.8(c)-.8(ond)-218.5(O)]TJ
7.3823 0 0 6.5614 515.225 498.7841 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 520.8943 500.4282 Tm
-.0154 Tc
[(reacts)-217.9(a)-.4(t)]TJ
-21.1151 -1.1116 TD
-.0159 Tc
[(C-)-15.9(1)10.7(5)-310.7(to)-316.5(f)-15.9(o)10.7(rm)-312(a)-317.7(15-hydrop)-15.9(e)15.3(r)-15.9(o)10.7(xyl)-316.6(radical,)-313.1(w)-.6(hich)-316.5(extracts)-316.3(a)-317.7(hy-)]TJ
T*
[(dr)-16(o)10.6(g).2(en)-293.6(from)-300.5(Tyr385)-299.3(to)-293.6(form)-300.5(PGG)]TJ
7.3823 0 0 6.5614 445.7762 476.9007 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 449.2912 478.5447 Tm
-.0159 Tc
[(.)-301.6(P).5(eroxidases)-299(s).5(uch)-293.5(a)-.9(s)-299(G)-.6(ST)]TJ
-13.8406 -1.1174 TD
[(per)-15.9(o)10.7(xidase)-306.1(may)-305(contr)-15.9(i)10.6(bute)-306.1(t).2(o)-310.7(t).2(he)-306.1(reduction)-310.7(of)-305(PGG)]TJ
7.3823 0 0 6.5614 512.3904 465.9589 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 518.9668 467.5463 Tm
-.0159 Tc
[(to)-310.7(PGH)]TJ
7.3823 0 0 6.5614 548.5038 465.9589 Tm
0 Tc
(2)Tj
9.843 0 0 9.843 313.0582 456.6046 Tm
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[(\()-16.1(1)10.5(49,)-278.7(150\))-282.1(\(Fig.)-278.7(2).1(B\).)]TJ
1.0137 -1.1116 TD
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[(CO)5.2(X)-277.1(i)5.9(s)-270.2(pre)4.9(sent)-270.6(i)5.9(n)-276.2(C)5(O)-.6(X)5.2(-).3(1)-270.4(\().3(PG)5.2(HS-)6.1(1).3(\))-270.4(a)-.9(n)6(d)-276.2(C)5(OX-)6.1(2)-270.4(\().3(PG)5.2(HS-)6.1(2).3(\))]TJ
-1.0137 -1.1116 TD
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[(isof)5.3(orms)-288.3(\()-.5(1)5.2(49\))5.3(.)-290.8(C)4.2(OX-)5.3(1)-288.5(i)-.6(s)-282.5(c)-1.7(on)5.2(stit)5.1(uti)5.1(v)-.5(ely)-288.5(e)4.1(xpressed)-288.5(i)-.6(n)-282.7(m)-1.8(os)5.4(t)-288.6(t)-.6(i)5.1(s)-.3(-)]TJ
0 -1.1174 TD
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[(sues)5.9(,)-186.7(w)4.9(hil)5.6(e)-185.5(COX-2)-178.6(e)-1.2(xp)5.7(res)5.9(s).2(ion)-178.6(i)-.1(s)-184.1(t)-.1(r)5.8(a)-1.2(ns)5.9(ien)5.7(tly)-178.6(and)-184.3(r)5.8(api)5.6(d)0(ly)-178.6(ind)5.7(u)0(ced)]TJ
0 -1.1116 TD
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[(in)-242.5(res)5.3(pon)5.1(se)-243.7(to)-242.5(a)-243.7(v)-.6(ariety)-242.5(of)-242.5(cell)-242.7(st)5(imuli)-242.7(s)-.4(u)5.1(c)-1.8(h)-242.5(a)-1.8(s)-242.3(p)-.6(r)5.2(o)-.6(in)5.1(ammato)5.1(r)-.6(y)]TJ
T*
-.0166 Tc
[(agents)5.5(,)-498.1(c)4.2(yto)5.3(k)-.4(in)5.3(es,)-492.3(a)-1.6(n)5.3(d)-495.8(gr)5.4(owt)5.2(h)-495.7(facto)5.3(r)-.4(s.)-492.3(In)-495.8(addi)5.2(tio)5.3(n)-.4(,)-492.3(C)-1.4(OX-2,)]TJ
0 -1.1174 TD
[(unl)5.1(ike)-278.1(o)5.2(ther)-277(oxy)5.2(genases)-276.8(i)-.6(n)-277(t)5.1(he)-278.1(ei)5.1(co)5.2(sano)5.2(id)-277(cascades,)-273.6(i)-.6(s)-276.8(u)-.5(p)5.2(r)-.5(eg)5.2(u-)]TJ
0 -1.1116 TD
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[(lat)5.8(e)-1(d)-276.3(b).2(y)-276.3(hyp)5.9(oxi)5.8(a)]TJ
/F6 1 Tf
6.7734 0 TD
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(via)Tj
/F5 1 Tf
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[(an)-276.7(HI)5.6(F-1)5.5(-depen)5.5(d)-.2(en)5.5(t)-276.8(mechanism)-277.9(\()5.6(81\))5.6(.)]TJ
-7.2169 -1.1116 TD
0 Tc
[(The)-264.9(action)-262.6(of)-267.1(PGs)-263(and)-263.7(TXA)]TJ
7.3823 0 0 6.5614 434.4944 367.3133 Tm
(2)Tj
9.843 0 0 9.843 440.7873 368.9574 Tm
[(is)-261.3(mediated)-267.2(through)-261.2(binding)]TJ
-12.9766 -1.1174 TD
[(to)-244.2(a)-244.2(series)-244.8(of)-244.1(G)-238.1(protein-coupled)-250.7(receptors)-243.7(\(GPCRs\),)-244.1(the)-246.5(PGE)]TJ
0 -1.1116 TD
[(recep)-9(tors:)-207.1(EP1)-211.7(\(E)-210.7(prostanoid)-208(recep)-9(tor)-205(1\),)-213(EP2,)-209.4(EP3,)-209.4(and)-211.8(EP4;)]TJ
T*
[(PGD)-402.3(receptors:)-400.4(DP1)-395.7(and)-401.9(DP2;)-396.9(PGF)-395.5(receptor:)-405.3(FP;)-394.8(PGI)-395.6(re-)]TJ
0 -1.1174 TD
[(cepto)-8(r:)-250(IP;)-256.7(and)-252.1(TXA)]TJ
7.3823 0 0 6.5614 394.0156 323.4897 Tm
(2)Tj
9.843 0 0 9.843 400.1952 325.0771 Tm
[(receptor:)-255.5(TP;)-257.9(on)-249.9(a)-255.7(variety)-257.9(of)-255.6(cell)-254.7(types)]TJ
-8.8527 -1.1116 TD
[(exerting)-287.8(a)-278.7(multitude)-283.5(of)-278.6(physiological)-287.7(functions)-281.8(\(Fig.)-278.5(1B\).)]TJ
/F3 1 Tf
8.9663 0 0 8.9663 313.0582 292.1952 Tm
[(Biosynthesis)-341.9(of)-330.2(Leukotrienes)]TJ
/F5 1 Tf
9.843 0 0 9.843 323.0361 275.7543 Tm
[(The)-673.8(canonical)-683(reaction)-674.9(was)-679(catalyzed)-678.3(by)-670.3(LOX)-680.1(iso-)]TJ
-1.0137 -1.1116 TD
[(xygenation)-353.4(of)-342(polyunsaturated)-348.5(fatty)-346.7(acids)-347.6(containing)-347.8(a)-347.8(1,4-)]TJ
/F6 1 Tf
0 -1.1174 TD
(cis)Tj
/F5 1 Tf
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[(-pentadiene)-201.3(st)20.9(ru)20.9(ct)13.8(ur)20.9(e.)-172.7(In)-180.7(th)20.7(e)-186.6(c)0(a)18.5(s)0(e)-176(o)0(f)-175(5)0(-)15.1(L)0(O)18.8(X)0(,)-172.4(o)0(x)20.8(y)0(g)15.1(e)0(n)19.7(a)0(t)19.6(i)0(o)20.7(n)-185.4(of)]TJ
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T*
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/F11 1 Tf
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(D)Tj
/F5 1 Tf
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(6-)Tj
/F6 1 Tf
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[(tr)20.9(an)20.8(s)]TJ
/F5 1 Tf
2.3672 0 TD
[(do)15.1(ub)20.8(le)-349.1(bo)20.8(nd)20.8(.)-360.5(T)0(h)19.6(e)-365.1(ra)19.7(di)20.7(ca)18.5(l)-358.3(a)0(t)-354.8(C)0(-)19.8(5)-358.2(re)19.7(ac)18.5(ts)-353.5(wi)19.8(th)-347.9(O)]TJ
7.3823 0 0 6.5614 537.3353 219.2881 Tm
(2)Tj
9.843 0 0 9.843 544.592 220.9322 Tm
(to)Tj
-23.5226 -1.1116 TD
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/F6 1 Tf
10.978 0 TD
[(tr)15.1(an)20.8(s)]TJ
/F5 1 Tf
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[(-8)20.9(,1)18.5(1,)18.5(14)20.8(-)]TJ
/F6 1 Tf
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[(ci)19.5(s)]TJ
/F5 1 Tf
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[(-e)19.7(ic)19.6(os)15.3(at)19.5(et)19.6(ra)19.7(en)19.7(oi)20.7(c)]TJ
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(4)Tj
9.843 0 0 9.843 527.5841 188.0503 Tm
.4988 Tc
[(.T)498.8(h)518.4(i)498.8(s)]TJ
-21.7947 -1.1116 TD
0 Tc
[(co)13.9(nv)20.8(er)19.7(si)20.9(on)-261.4(in)20.7(vo)15.1(lv)20.7(es)-262.4(an)-262.5(in)20.7(it)14.8(ia)19.5(l)-271.9(a)0(b)19.7(s)0(t)20.9(r)0(a)19.7(c)0(t)19.6(i)0(o)15(n)-271.8(of)-261.4(th)20.7(e)-273(p)0(r)20.9(o)0(-)15.1(R)-272.8(hy)20.8(dr)20.9(o-)]TJ
T*
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T*
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/F11 1 Tf
15.5915 0 TD
(D)Tj
/F5 1 Tf
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[(7,)18.5(9-)]TJ
/F6 1 Tf
1.5436 0 TD
[(tr)20.9(an)20.8(s)]TJ
/F5 1 Tf
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[(yi)20.7(el)19.5(di)20.7(ng)-399.6(a)]TJ
-20.2166 -1.1174 TD
[(co)13.9(nj)20.7(ug)20.8(at)19.5(ed)-262.5(tr)15(ie)19.6(ne)-262.5(sy)21(st)15.1(em)18.5(,)-274.1(w)0(h)20(i)0(c)19.5(h)-271.8(is)-267.1(th)20.7(e)-278.7(p)0(h)20.8(y)0(s)21(i)0(c)19.5(o)0(c)19.7(h)0(e)19.7(m)0(i)19.5(c)0(a)18.5(l)-277.7(ba)19.7(si)20.9(s)]TJ
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[(fo)15.1(r)-346.6(t)0(h)20.7(e)-353.6(ty)20.7(pi)20.7(ca)18.5(l)-346.8(l)0(e)19.6(u)0(k)15.1(o)0(t)20.7(r)0(i)20.7(e)0(n)19.7(e)-347.8(ch)19.7(ro)15.1(m)15(o)0(p)15.1(h)0(o)20.8(r)0(e)19.7(.)-349(Fi)20.9(na)19.7(ll)20.6(y,)-338.6(th)20.7(e)-353.6(r)0(a)19.7(d)0(i)20.7(c)0(a)18.5(l)]TJ
T*
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(4)Tj
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[(\(5)15.1(2\))-232.6(\(F)21(ig)20.7(.)-239.6(2)0(C)19.8(\))0(.)]TJ
-17.5613 -1.1116 TD
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[(ti)14.8(va)19.7(te)19.5(d)-191.2(b)0(y)-175(C)0(a)]TJ
/F9 1 Tf
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(++)Tj
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T*
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/F3 1 Tf
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(276)Tj
46.897 0 TD
(ARAU)Tj
2.3521 .2087 TD
()Tj
.5248 -.2087 TD
[(JO)-329.9(ET)-338.7(AL.)]TJ
ET
endstream
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BT
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[(cellular)-398.1(C)-.4(OX)-397.7(and)-396.7(L)-.6(OX)-397.7(bio-)]TJ
0 -1.0077 TD
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[(synthesis.)-307.4(\(A\).)]TJ
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[(This)-304.6(scheme)-305.9(il-)]TJ
-6.0119 -1.0135 TD
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[(lustrates)-195.5(t)0(he)-196.8(major)-195.7(p).1(athways)-195.5(for)]TJ
T*
-.0217 Tc
[(production)-333.7(o).3(f)-333.7(t).2(he)-334.8(main)-333.7(e)-.8(icosa-)]TJ
T*
[(noids)-183.9(discussed.)-180.7(AA)-179.1(is)-183.9(substrate)]TJ
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[(for)-449(oxidation)-449(b).1(y)-449(lipoxygenase)]TJ
0 -1.0135 TD
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[(\(LOX;)-944.1(5-LOX)-939(and)-944(12/15-)]TJ
T*
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[(LOX\),)-750.3(C)5.5(OX)-748.7(and)-747.9(C)-.3(YP)-747.7(en-)]TJ
T*
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[(zymes,)-1286(w)-.3(hich)-1283.6(collectively)]TJ
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[(produce)-271.6(a)-265.8(large)-265.8(spectrum)-265.8(of)-270.4(ei-)]TJ
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(cosanoids.)Tj
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(\(B\).)Tj
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[(Cellular)-483.1(C)-.4(OX)]TJ
-6.4381 -1.0135 TD
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[(biosynthesis.)-796.9(COX)-795.4(catalyzes)]TJ
T*
-.0221 Tc
[(the)-611.6(formation)-604.7(o)-.1(f)-610.5(P).1(GG)]TJ
7.3837 0 0 6.5625 152.844 615.2313 Tm
0 Tc
(2)Tj
9.845 0 0 9.845 156.3023 616.8187 Tm
.585 Tc
[(,a)605.9(n)607(d)]TJ
-9.8068 -1.0077 TD
-.022 Tc
[(then,)-906.4(s).2(ubsequent)-904.2(peroxidase)]TJ
0 -1.0135 TD
-.0218 Tc
[(activity)-535.3(furth)6(e)-.9(r)-535.3(c)-.9(onverts)-529.4(i).1(t)-535.5(t).1(o)]TJ
T*
(PGH)Tj
7.3837 0 0 6.5625 78.6897 585.2975 Tm
0 Tc
(2)Tj
9.845 0 0 9.845 82.2047 586.9416 Tm
-.0219 Tc
[(.)-756.6(F).3(rom)-755.4(this)-754.1(precursor,)]TJ
-2.2804 -1.0077 TD
[(downstream)-686.2(enzymes)-684.9(initiate)]TJ
0 -1.0135 TD
[(the)-565.3(produ)6(ction)-564.1(o).2(f)-558.3(prostaglan-)]TJ
T*
[(dins)-328(and)-328.2(t)-.1(hromboxanes,)-330.6(whose)]TJ
T*
-.0216 Tc
[(bioactions)-759.5(are)-760.9(mediated)]TJ
/F6 1 Tf
10.8606 0 TD
-.0214 Tc
(via)Tj
/F5 1 Tf
-10.8606 -1.0077 TD
-.0218 Tc
[(signaling)-1404.8(t).1(hrou)6(gh)-1404.8(distinct)]TJ
0 -1.0135 TD
-.0215 Tc
[(GPCRs.)-485.6(T)-.6(hese)-484.4(COX)-484(metabo-)]TJ
T*
-.0223 Tc
[(lites)-460.8(a)-1.4(re)-462.1(exported)-460.9(through)-460.9(the)]TJ
T*
-.0215 Tc
[(plasma)-190.7(me)5.1(mbrane)]TJ
/F6 1 Tf
7.1521 0 TD
(via)Tj
/F5 1 Tf
1.3475 0 TD
[(an)-189.6(export)]TJ
-8.4996 -1.0077 TD
[(carrier)-229.9(known)-229.9(a)-.7(s)-229.7(P).6(GT,)-226.5(a)-.7(nd)-229.9(thus)]TJ
0 -1.0135 TD
[(secreted)-529.2(to)-523.5(reach)-523.5(their)-529.2(c)-.6(orre-)]TJ
T*
-.0218 Tc
[(sponding)-454.7(receptors)-448.8(on)-454.7(diverse)]TJ
0 -1.0077 TD
-.0215 Tc
[(target)-310.6(cells)-310.3(to)-310.4(el)6.1(icit)-310.6(an)-310.4(array)-310.4(o).5(f)]TJ
0 -1.0135 TD
-.0218 Tc
[(physiological)-719.8(responses.)]TJ
/F7 1 Tf
10.4748 0 TD
-.0216 Tc
(\(C\))Tj
/F5 1 Tf
1.3187 0 TD
0 Tc
(.)Tj
-11.7935 -1.0135 TD
-.0218 Tc
[(Cellular)-460.4(L)-.9(T)-461.6(b)6(iosynthesis.)-462.8(Un-)]TJ
T*
[(der)-472(cellular)-472(s).4(timulation,)-474.3(intra-)]TJ
0 -1.0077 TD
-.0215 Tc
[(cellular)-972.7(C)-.5(a)]TJ
7.3837 0 0 6.5625 107.8866 431.9432 Tm
0 Tc
(2)Tj
/F9 1 Tf
.4684 0 TD
(+)Tj
/F5 1 Tf
9.845 0 0 9.845 124.7811 427.5778 Tm
-.0216 Tc
[(is)-978.3(in)6.2(creased,)]TJ
-6.6051 -1.0135 TD
-.0219 Tc
[(thus)-443.1(activating)-443.3(a)-1(nd)-437.5(translocat-)]TJ
T*
-.0216 Tc
[(ing)-310.5(c)-.7(PLA2)]TJ
/F10 1 Tf
4.2498 0 TD
0 Tc
(a)Tj
/F5 1 Tf
.7889 0 TD
-.0216 Tc
[(and)-304.8(5-LOX)-311.3(to)-310.5(the)]TJ
-5.0387 -1.0135 TD
-.0214 Tc
[(nuclear)-356.4(membrane.)-353(T)-.5(here,)-358.8(A)-.2(A)]TJ
0 -1.0077 TD
-.0218 Tc
[(is)-247.2(released)-241.6(from)-248.5(membrane)-248.5(and)]TJ
0 -1.0135 TD
-.0214 Tc
[(converted)-390.9(to)-385.2(LTA)]TJ
7.3837 0 0 6.5625 130.2236 376.1007 Tm
0 Tc
(4)Tj
9.845 0 0 9.845 137.537 377.7448 Tm
-.0216 Tc
[(by)-391.1(5-LOX)]TJ
-7.9007 -1.0135 TD
-.0218 Tc
[(and)-1353(F).4(LAP.)-1355.4(Sub)6(s)-5.3(e)4.8(quently,)]TJ
T*
-.0209 Tc
(LTA)Tj
7.3837 0 0 6.5625 78.2929 356.2015 Tm
0 Tc
(4)Tj
9.845 0 0 9.845 83.8488 357.7889 Tm
-.0214 Tc
[(is)-206.5(metaboli)6.2(zed)-212.4(int)6.2(o)-212.4(LT)5.2(B)]TJ
7.3837 0 0 6.5625 174.6141 356.2015 Tm
0 Tc
(4)Tj
9.845 0 0 9.845 59.7543 347.8676 Tm
-.0229 Tc
[(or)-622.8(LTC)]TJ
7.3837 0 0 6.5625 91.6157 346.2235 Tm
0 Tc
(4)Tj
9.845 0 0 9.845 101.1968 347.8676 Tm
-.0217 Tc
[(by)-615.8(the)-617(LTA4H)-616.6(or)]TJ
-4.2095 -1.0135 TD
[(LTC4S)-391(enzymes,)-393.5(r).4(espe)5(ctively.)]TJ
T*
[(LTs)-465.9(are)-461.5(e)-.8(xported)-460.3(through)-466.1(the)]TJ
0 -1.0077 TD
-.0215 Tc
[(plasma)-190.7(me)5.1(mbrane)]TJ
/F6 1 Tf
7.1521 0 TD
(via)Tj
/F5 1 Tf
1.3475 0 TD
[(an)-189.6(export)]TJ
-8.4996 -1.0135 TD
-.0219 Tc
[(carrier)-282(known)-282(a)-1(s)-281.9(M)-.7(RP,)-284.4(a)-1(nd)-282(se-)]TJ
T*
-.0213 Tc
[(creted)-678.8(LT)5.3(s)-678.6(t).6(hen)-678.8(r).7(e)5.3(ach)-678.8(their)]TJ
T*
-.022 Tc
[(corresponding)-1076.8(receptors)-1076.6(on)]TJ
0 -1.0077 TD
-.0215 Tc
[(diverse)-518.9(t).4(arget)-512.1(cells.)-520.1(AA,)-514.4(ara-)]TJ
0 -1.0135 TD
[(chidonic)-749.3(acid;)-748.3(COX,)-750.6(cyclo-)]TJ
T*
-.0217 Tc
[(oxygenase;)-558.4(C)-.7(YP,)-554.9(c)-.8(ytochrome)]TJ
T*
-.0221 Tc
[(P450;)-1388(DHET,)-1384.5(dihydroxy-)]TJ
0 -1.0077 TD
-.0215 Tc
[(eicosatrienoic)-1267.5(acids;)-1266.5(E)5.1(ET,)]TJ
0 -1.0135 TD
-.0217 Tc
[(epoxyeicosatrienoic)-2200.6(acids;)]TJ
T*
[(FLAP,)-393.6(5-lipoxygenase)-392.4(activat-)]TJ
0 -1.0077 TD
[(ing)-264.7(protein;)-264.8(GPCRs,)-261.3(G)-265.5(protein-)]TJ
0 -1.0135 TD
-.0215 Tc
[(coupled)-1099.3(receptors;)-1099.5(H)-.3(E)5.1(TEs,)]TJ
T*
-.0217 Tc
[(hydroxy-eicosatetraenoic)-196.6(acids;)]TJ
T*
[(HpETEs,)-1706.6(hydroperoxyeico-)]TJ
0 -1.0077 TD
[(satetraenoic)-403.9(a)4.9(cids;)-402.9(M)-.5(RP,)-399.4(m)-.8(ul-)]TJ
0 -1.0135 TD
[(tidrug)-552.5(r)-5.4(e)4.9(sis)-5.2(t)5.9(ance)-553.7(protein;)-552.7(LT,)]TJ
T*
-.0219 Tc
[(leukotriene;)-276.4(LTA)]TJ
7.3837 0 0 6.5625 125.6315 146.948 Tm
0 Tc
(4)Tj
9.845 0 0 9.845 129.1464 148.5921 Tm
-.021 Tc
[(H,)-272(LTA)]TJ
7.3837 0 0 6.5625 159.4771 146.948 Tm
0 Tc
(4)Tj
9.845 0 0 9.845 165.6566 148.5921 Tm
-.022 Tc
(hy-)Tj
-10.757 -1.0135 TD
-.0218 Tc
[(drolase;)-765.8(LOX,)-762.3(lipoxygenase;)]TJ
0 -1.0077 TD
[(LXs,)-687.3(lipoxin)6.1(s)-5.2(;)-679.3(P).5(GH,)-687.3(prosta-)]TJ
0 -1.0135 TD
[(glandin)-333.7(H)-.5(;)-328.1(P).5(GT,)-330.3(prostaglandin)]TJ
T*
[(transporter;)-604.5(P).5(LA)]TJ
7.3837 0 0 6.5625 126.4819 113.1024 Tm
0 Tc
(2)Tj
9.845 0 0 9.845 129.9968 108.737 Tm
-.022 Tc
[(,)-601.2(phospholi-)]TJ
-7.1348 -1.0077 TD
-.0218 Tc
[(pase)-173.7(A)]TJ
7.3837 0 0 6.5625 84.9826 103.1811 Tm
0 Tc
(2)Tj
9.845 0 0 9.845 90.1417 98.8157 Tm
-.0217 Tc
[(superfamily.)-169(T)-.8(o)-172.4(s).5(ee)-173.6(this)]TJ
-3.0866 -1.0135 TD
[(illustration)-172.4(i).2(n)-172.4(c)4.9(olor,)-174.8(the)-167.8(r).3(eader)-172.4(is)]TJ
T*
[(referred)-391.2(t).2(o)-385.5(t).2(he)-386.7(web)-385.5(v).3(ersion)-391.2(of)]TJ
T*
[(this)-483.3(article)-478.9(at)-483.7(www.liebertpub)]TJ
0 -1.0077 TD
-.02 Tc
[(.com/a)6.6(rs)]TJ
ET
q
1 i
190.261 733.549 m
550.828 733.549 l
550.828 72.51 l
190.261 72.51 l
W n
q
360.926 0 0 661.039 190.261 72.51 cm
/Im2 Do
Q
Q
BT
/F3 1 Tf
8.9663 0 0 8.9663 297.4109 34.2425 Tm
0 Tc
(277)Tj
ET
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