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[(gi)18.9(ft)-318.5(fr)12.4(om)-317.7(Ja)19.6(ns)14.4(se)19.6(n)-325.1(P)0(h)16.3(a)0(r)13.5(m)0(a)17.7(c)0(e)20.4(u)0(t)13.2(i)13.9(ca)-321(NV)138.6(,)-324.7(B)0(e)16.1(e)0(r)19.2(s)0(e)13.9(,)-324.7(Be)16.1(lg)18.9(iu)18.9(m\))-324.9(1)]TJ 0 -1.0471 TD [(mm)14.9(ol)]TJ /F11 1 Tf 2.2762 0.1992 TD (.)Tj /F3 1 Tf 0.2731 -0.1992 TD (L)Tj 7.472 0 0 6.641 89.575 343.162 Tm (-1)Tj 9.963 0 0 9.963 95.584 338.74 Tm [(,)-398.7(b)0(o)15.5(t)0(h)-396.6(f)0(o)19.6(r)-406.4(2)-404.8(m)0(i)15.7(n)0(.)-393.8(T)0(h)17.1(e)-405.2(na)15.1(sa)19.6(l)-407.2(P)11.4(D)-403(w)0(a)11.2(s)-400.3(me)12(as)19.6(ur)19.6(ed)]TJ -3.7444 -1.0528 TD [(af)19.2(te)12.8(r)-218.6(t)13.9(he)-212.5(co)20.8(mp)12.4(le)18.4(ti)16.5(on)-206.4(of)-208(ne)15.1(bu)21.2(li)16.5(za)14.7(ti)16.5(on)21.2(;)-219.4(3)0(\))-208(a)-217.4(su)14.4(bg)21.2(ro)13.9(up)-206.4(of)-208(ei)18.4(gh)15.5(t)]TJ 0 -1.0471 TD [(mi)15.7(ce)-690.9(\(f)18(ou)15.5(r)-696.6(c)0(o)15.1(n)0(t)18.9(r)0(o)19.6(l)-703.1(an)20.8(im)15.7(al)18.4(s)-701.9(a)0(n)20.8(d)-700.7(fo)19.6(ur)-691.7(in)18.9(se)13.9(rt)17.3(io)18.8(na)20.8(l)-703.1(C)11.6(F)]TJ 0 -1.0528 TD [(an)15.1(im)21.4(al)12.8(s\))-414(we)16.9(re)-418.9(ad)15.1(mi)15.7(ni)18.9(st)17.7(er)19.2(ed)-417.3(ne)15.1(bu)15.5(l)13.9(i)0(z)12.8(e)0(d)-417.3(s)0(o)20(d)0(i)18.9(u)0(m)-420.1(g)0(l)18.9(u)0(c)15.1(o)0(n)21.2(a)0(t)12.8(e)]TJ 0 -1.0471 TD [(\(C)14.9(l)]TJ 7.472 0 0 6.641 70.583 301.323 Tm (-)Tj 9.963 0 0 9.963 76.876 296.901 Tm [(fr)12.4(ee)-383.6(ve)15.1(hi)18.9(cl)18.5(e\))-384.8(0.)15.9(15)-382.8(mo)18.1(l)]TJ /F11 1 Tf 9.0252 0.1992 TD (.)Tj /F3 1 Tf 0.2731 -0.1992 TD (L)Tj 7.472 0 0 6.641 175.465 301.323 Tm (-1)Tj 9.963 0 0 9.963 185.442 296.901 Tm [(af)19.2(te)18.4(r)-395(t)0(h)18.9(e)-399.5(so)20(di)18.9(um)-385.9(ch)15.1(an)20.8(ne)15.1(l)]TJ -12.7639 -1.0527 TD [(bl)18.9(oc)15.1(ke)20.8(r;)-443.7(4\))-441.3(fi)11.6(na)20.8(ll)16.5(y)-450.3(n)0(e)15.1(b)0(u)21.2(l)0(i)16.5(z)0(e)14.7(d)-450.3(UT)18.9(P)-455.2(\()0(S)20.4(i)0(g)18.9(m)0(a)12(,)-449.9(U)12.4(K)0(\))-445.2(0)0(.)15.9(1)0(\261)21.2(1)0(0)]TJ 0 -1.0471 TD [(mm)14.9(ol)]TJ /F11 1 Tf 2.2762 0.1992 TD (.)Tj /F3 1 Tf 0.2731 -0.1992 TD (L)Tj 7.472 0 0 6.641 89.575 280.403 Tm (-1)Tj 9.963 0 0 9.963 97.682 275.981 Tm [(di)18.9(ss)13.2(ol)18.9(ve)20.8(d)-205.6(i)0(n)-197.4(0)0(.)15.9(1)0(5)-195(M)-207.6(so)20(di)13.2(um)-192.5(gl)13.2(uc)20.8(on)15.5(at)18.4(e)-206(w)0(a)16.9(s)-206.8(gi)18.9(ve)15.1(n)]TJ -3.9549 -1.0527 TD [(to)-430.7(al)18.4(l)-441.3(m)0(i)15.7(c)0(e)-429.1(i)0(n)-430.7(g)0(r)13.9(o)0(u)21.2(p)0(s)-435.2(a)0(\))-430.3(a)0(n)20.8(d)-438.9(b\))-435.6(an)20.8(d)-438.9(t)0(h)13.2(e)-439.3(P)11.4(D)-442.9(wa)16.9(s)-440.1(a)0(g)20.8(a)0(i)12.8(n)]TJ 0 -1.0471 TD [(me)17.7(as)14(ur)19.6(ed)15.1(.)-495.5(A)0(f)15.7(t)0(e)18.4(r)-503.1(ea)14.7(ch)-491.3(ex)20.8(pe)15.1(ri)17.3(me)17.7(nt)-493.3(th)18.9(e)-501.9(m)0(i)15.7(c)0(e)-491.7(w)0(e)16.9(r)0(e)-492.9(g)0(i)18.9(v)0(e)15.1(n)]TJ 0 -1.0527 TD [(at)18.4(ip)18.9(am)12(ez)20.4(ol)18.9(e)-217.4(0)0(.)21.6(2)0(5)-200.7(m)0(g)]TJ /F11 1 Tf 8.0806 0.1992 TD (.)Tj /F3 1 Tf 0.2675 -0.1992 TD [(30)-206.4(g)-211.3(b)0(o)21.2(d)0(y)-206.4(w)12.4(ei)12.8(gh)21.2(t)]TJ 7.472 0 0 6.641 208.63 248.995 Tm (-1)Tj 9.963 0 0 9.963 216.794 244.573 Tm [(as)-202.3(an)15.1(ti)16.5(do)21.2(te)-203.5(fo)13.9(r)-207.2(t)0(h)13.2(e)]TJ -15.9108 -1.0471 TD [(me)17.7(t-)17.3(et)18.4(om)12.4(id)18.9(at)18.5(e)-484.9(t)13.9(o)-484.5(e)0(n)20.8(a)0(b)15.1(l)0(e)-470.9(t)0(h)13.2(e)0(m)-471.7(t)0(o)-470.5(r)0(e)13.5(c)0(o)20.8(v)0(e)15.1(r)-480.4(mo)18.1(re)-475.8(qu)21.2(ic)18.4(kl)13.2(y)]TJ 0 -1.0527 TD [(fr)18(om)-317.7(th)18.9(e)-325.5(a)0(n)15.1(a)0(e)20.4(s)0(t)17.7(h)0(e)15.1(t)0(i)16.5(c)0(.)]TJ 1.0015 -1.0471 TD [(A)-243.7(M)0(a)18.9(n)0(n)-234.8(W)0(h)14.4(i)0(t)16.5(n)0(e)20.8(y)-245.5(U)12.4(-)0(t)17.3(e)0(s)13.9(t)-242.1(wa)16.9(s)-241(u)0(s)14.4(e)0(d)-229.6(t)0(o)-237.2(a)0(s)19.6(s)0(e)13.9(s)0(s)-231.5(s)0(i)17.7(g)0(n)15.5(i)13.9(fi)11.6(ca)20.4(nc)15.1(e)]TJ -1.0015 -1.0528 TD [(be)15.1(tw)20.6(ee)14.7(n)-359.3(g)0(r)13.9(o)0(u)21.2(p)0(s)-355.5(a)0(n)15.1(d)-359.3(W)37.9(i)0(l)16.5(c)0(o)20.8(x)0(o)15.5(n)-359.3(si)17.7(gn)15.5(ed)-354.8(ra)19.2(nk)-354.3(te)18.4(st)-352.2(to)-356.7(as)19.6(se)13.9(ss)]TJ 0 -1.0471 TD [(si)17.7(gn)15.5(if)17.3(ic)18.4(an)20.8(ce)-281.2(wi)14.9(th)18.9(in)-277.1(th)18.9(e)-291.4(g)0(r)19.6(o)0(u)21.2(p)0(s)14.4(.)-284.9(A)-289.2(p)0(r)19.6(o)0(j)13.2(e)0(c)20.4(t)-287.7(li)16.5(ce)20.4(nc)15.1(e)-285.7(a)0(p)15.1(p)0(r)19.6(o)0(v)15.5(a)0(l)]TJ 0 -1.0528 TD [(wa)16.9(s)-536.9(o)0(b)21.2(t)0(a)18.4(i)0(n)13.2(e)0(d)-519.8(f)0(r)12.4(o)0(m)-522.5(t)0(h)18.9(e)-536.1(Ho)17.3(me)-528.6(O)12.4(f)14.7(fi)17.3(ce)-525.9(to)-521.8(ca)14.7(rr)18(y)-535.7(o)0(u)21.2(t)-532.4(th)13.2(e)]TJ 0 -1.0471 TD [(pr)19.6(oc)15.1(ed)15.1(ur)19.6(es)19.6(.)]TJ /F6 1 Tf 9.8617 -3.0103 TD (Results)Tj /F3 1 Tf -8.8602 -1.8494 TD [(Na)16.9(sa)13.9(l)-270.6(m)0(e)17.7(m)0(b)18.1(r)0(a)13.5(n)0(e)-258(P)0(D)-266.4(i)0(n)-260(m)0(i)15.7(c)0(e)-264.1(w)0(e)16.9(r)0(e)-265.3(l)0(u)18.9(m)0(e)17.7(n)-273.9(ne)20.8(ga)15.1(ti)16.5(ve)20.8(.)-273.5(T)12.2(he)]TJ -1.0015 -1.0471 TD [(re)19.2(st)17.7(in)13.2(g)-256.8(n)0(a)20.8(s)0(a)13.9(l)-253.5(ep)15.1(it)16.5(he)20.8(li)16.5(al)-249(P)11.4(D)-260.8(in)-248.6(co)20.8(nt)18.9(ro)13.9(ls)-244.1(ra)13.5(ng)21.2(ed)-252.3(-1)19.6(2\261)-149.5(-2)19.6(7)-256.8(m)0(V)]TJ 25.1977 46.4918 TD [(\(m)16.5(ed)15.1(ia)18.4(n)-376.3(-)0(2)19.6(0)-376.3(mV)139.3(,)-370.3(n)]TJ /F9 1 Tf 7.6993 0 TD (=)Tj /F3 1 Tf 0.5463 0 TD [(20)21.2(\))-377.9(a)0(n)20.8(d)-376.3(in)]TJ /F4 1 Tf 4.6093 0 TD [(cf)18.5(tr)]TJ /F3 1 Tf 7.472 0 0 6.641 450.595 580.138 Tm [(tm)23.3(1H)26.8(GU)]TJ 9.963 0 0 9.963 481.493 575.716 Tm [(mi)21.4(ce)-366.5(-1)14(8\261)-149.5(-3)19.6(8)]TJ -17.2822 -1.0755 TD [(mV)-219.2(\(m)16.5(ed)20.8(ia)18.4(n)-222.7(-)0(2)13.9(8)-217(mV)139.3(,)-222.3(n)]TJ /F9 1 Tf 8.9455 0 TD (=)Tj /F3 1 Tf 0.5463 0 TD [(24)21.2(\).)-213.3(Th)17.1(e)]TJ /F8 1 Tf 3.5111 0 TD (D)Tj /F3 1 Tf 0.6544 0 TD [(F5)16.3(08)-212.1(mi)15.7(ce)-212.9(ha)15.1(d)-217(a)-223.1(hi)18.9(gh)15.5(er)]TJ -13.6573 -1.0755 TD [(ba)15.1(sa)19.6(l)-327.5(P)11.4(D)-329.1(\()0(r)18(a)0(n)20.8(g)0(e)-314.9(-)0(2)13.9(5)0(\261)-149.5(-)0(3)19.6(9)-325.1(mV)139.3(,)-319.1(m)0(e)12(d)0(i)18.8(a)0(n)-314.9(-)0(3)19.6(4)-325.1(mV)139.3(,)-324.7(n)]TJ /F9 1 Tf 19.4446 0 TD (=)Tj /F3 1 Tf 0.5406 0 TD [(7\))13.9(.)]TJ -18.9837 -1.0527 TD [(Th)17.1(e)-314.2(c)0(h)20.8(a)0(n)15.1(g)0(e)20.8(s)-309.2(in)-299.8(na)15.1(sa)19.6(l)-310.4(P)11.4(D)-312(a)0(f)19.2(t)0(e)12.8(r)-309.7(am)17.7(il)16.5(or)19.6(id)18.9(e)-308.5(o)0(r)-304.7(l)0(o)18.8(p)0(e)20.8(r)0(a)13.5(m)0(i)15.7(d)0(e)]TJ -1.0015 -1.0755 TD [(ad)15.1(mi)15.7(ni)18.9(st)17.7(ra)19.2(ti)16.5(on)-473.8(we)16.9(re)-475.8(si)17.7(gn)21.2(if)17.3(ic)18.4(an)15.1(t)-481.2(i)0(n)-470.5(b)0(o)15.5(t)0(h)-470.5(C)0(F)-472.1(a)0(n)15.1(d)-478.8(co)15.1(nt)18.9(ro)19.6(l)]TJ T* [(gr)13.9(ou)21.2(ps)-378.3(\(p)]TJ /F9 1 Tf 3.8525 0 TD (<)Tj /F3 1 Tf 0.5463 0 TD [(0.)21.6(01)15.5(\))-383.6(c)0(o)15.1(m)0(p)18.1(a)0(t)18.4(i)0(b)13.2(l)13.9(e)-388.1(w)0(i)14.9(t)0(h)-373.8(s)0(o)14.3(d)0(i)18.9(u)0(m)-374.6(c)0(h)15.1(a)0(n)20.8(n)0(e)15.1(l)-384.4(bl)18.9(oc)15.1(k-)]TJ -4.3988 -1.0698 TD [(ad)15.1(e.)-559.2(No)-557.4(si)17.7(gn)15.5(if)17.3(ic)18.4(an)15.1(t)-566.5(P)11.4(D)-573.8(c)0(h)20.8(a)0(n)15.1(g)0(e)20.8(s)-571(w)12.4(e)0(r)13.5(e)-564.5(ob)15.5(se)19.6(rv)13.9(ed)-559.6(w)12.4(h)0(e)15.1(n)]TJ 0 -1.0755 TD [(so)14.4(di)18.9(um)-249.4(gl)18.9(uc)15.1(on)21.2(at)18.4(e)-257.2(\()0(l)17.3(o)0(w)-250.2(c)0(h)15.1(l)13.9(or)13.9(id)18.8(e)-257.2(v)0(e)15.1(h)0(i)18.9(c)0(l)18.5(e)0(\))-248.2(w)0(a)16.9(s)-258(ad)20.8(mi)15.7(ni)18.9(st)17.7(er)13.5(ed)]TJ T* [(af)13.5(te)18.4(r)-548.7(t)0(h)13.2(e)-547.5(so)14.4(di)18.9(um)-539.6(ch)15.1(an)15.1(ne)20.8(l)-549.4(b)0(l)13.2(o)0(c)20.8(k)0(e)15.1(r)0(s)18.4(.)-546.7(Su)16.3(bs)14.3(eq)20.8(ue)15.1(nt)18.9(ly)-538.8(UT)13.2(P)]TJ T* [(di)13.2(ss)18.8(ol)18.9(ve)15.1(d)-421.9(i)0(n)-419.3(0)0(.)15.9(1)0(5)-416.9(M)-423.8(so)14.3(di)18.9(um)-420.1(gl)18.9(uc)20.8(on)15.5(at)18.5(e)-428(i)0(n)18.9(c)0(r)13.5(e)0(a)20.4(s)0(e)14(d)-421.9(PD)-420.1(in)]TJ T* [(bo)15.5(th)-390.9(gr)14(ou)21.2(ps)14.4(,)-398.7(i)0(n)13.2(d)0(i)18.9(c)0(a)20.4(t)0(i)16.5(n)0(g)-394.2(t)0(h)18.9(a)0(t)-397(C)11.6(a)]TJ 7.472 0 0 6.641 435.572 473.272 Tm (2+)Tj 9.963 0 0 9.963 447.364 468.85 Tm [(ac)14.7(ti)16.5(va)20.8(te)12.8(d)-399.1(C)0(l)]TJ 7.472 0 0 6.641 495.326 473.272 Tm (-)Tj 9.963 0 0 9.963 501.732 468.85 Tm [(se)19.6(cr)13.5(et)18.5(io)18.8(n)]TJ -19.3137 -1.0755 TD [(wa)16.9(s)-417.4(o)0(c)15.1(c)0(u)15.1(r)0(r)18(i)0(n)18.9(g)0(.)-405.2(U)0(T)13.2(P)-415.4(gi)18.9(ve)15.1(n)-416.2(i)0(n)-407.9(0)0(.)15.9(9)0(%)-407.9(s)0(a)19.6(l)0(i)16.5(n)0(e)-411.7(s)0(o)20(l)0(u)18.8(t)0(i)16.5(o)0(n)-411.3(a)0(f)19.2(t)0(e)18.4(r)]TJ T* [(so)14.4(di)18.9(um)-294.9(ch)15.1(an)20.8(ne)15.1(l)-304.7(b)0(l)18.8(o)0(c)20.8(k)0(e)15.1(r)0(s)-294.5(w)0(e)16.9(r)0(e)-293.8(a)0(d)15.1(m)0(i)15.7(n)0(i)18.9(s)0(t)17.7(e)0(r)13.5(e)0(d)-292.1(h)0(a)15.1(d)-302.4(no)-291.8(ef)24.9(fe)19.2(ct)]TJ T* [(on)-405.6(P)11.4(D)0(.)-403.4(T)0(h)17.1(e)-410.9(PD)-403(ch)15.1(an)20.8(ge)15.1(s)-411.7(a)0(f)19.2(t)0(e)18.4(r)-412.1(am)17.7(il)16.5(or)13.9(id)18.9(e/)18.4(lo)18.8(pe)15.1(ra)19.2(mi)15.7(de)-400.3(an)15.1(d)]TJ T* [(UT)13.2(P)-210.5(a)0(d)15.1(m)0(i)15.7(n)0(i)18.9(s)0(t)17.7(r)0(a)19.2(t)0(i)16.5(o)0(n)-206.4(w)0(e)16.9(r)0(e)-208.4(s)0(i)17.7(g)0(n)21.2(i)0(f)17.3(i)0(c)12.8(a)0(n)20.8(t)-213.7(in)-208.8(t)13.9(h)0(e)]TJ /F4 1 Tf 16.6449 0 TD [(cf)18.4(tr)]TJ /F3 1 Tf 7.472 0 0 6.641 488.353 430.412 Tm [(tm)23.3(1H)19.2(GU)]TJ 9.963 0 0 9.963 517.663 425.99 Tm [(mi)15.7(ce)]TJ -20.9128 -1.0755 TD [(co)15.1(mp)18.1(ar)13.5(ed)-240.9(to)-248.6(co)20.8(nt)13.2(ro)19.6(ls)-244.1(\(p)]TJ /F9 1 Tf 9.2984 0 TD (<)Tj /F3 1 Tf 0.5406 0 TD [(0.)15.9(01)21.2(,)-256.5(t)0(a)18.4(b)0(l)18.9(e)0(s)-247.8(1)-256.8(and)-264.5(2\).)-265.3(Similar)-272.9(but)]TJ -9.839 -1.0755 TD [(larger)-426.4(PD)-431.5(responses)-433.9(were)-430.5(obtai)-9(ned)-429.5(in)-425(the)]TJ /F8 1 Tf 17.7318 0 TD (D)Tj /F3 1 Tf 0.6658 0 TD [(F5)-6.4(08)-428.3(mice)]TJ -18.3975 -1.0698 TD [(wi)-7.8(th)-316.9(sodiu)-7.4(m)-316.9(cha)-8.8(nnel)-318.8(blocki)-9.7(ng)-320.2(agents)-321.9(and)-321.4(UTP)-322.5(\(tables)-326.7(1)]TJ 0 -1.0755 TD [(and)-429.5(2\).)-430.3(An)-432.3(examp)-7.8(le)-425.4(of)-429.9(PD)-431.5(changes)-434.5(observed)-430.8(wi)-7.8(th)-425(the)]TJ T* [(abo)-8.4(ve)-303.5(c)-6.9(ombination)-12.6(s)-303.6(o)0(f)-310.4(drugs)-313.9(are)-312(shown)-310.5(in)-311.2(figures)-314.1(1)-308.1(and)]TJ T* (2.)Tj 1.0015 -1.0527 TD [(Th)17.1(e)-331.2(d)0(u)15.5(r)0(a)19.2(t)0(i)16.5(o)0(n)-320.2(o)0(f)-321.8(a)0(c)20.4(t)0(i)16.5(o)0(n)-320.2(o)0(f)-321.8(U)0(T)18.9(P)-330(\(w)15.7(it)16.5(h)-330.8(t)0(h)18.9(e)-331.2(na)20.8(sa)13.9(l)-327.5(m)0(u)18.1(c)0(o)15.1(s)0(a)]TJ -1.0015 -1.0755 TD [(in)-242.9(so)20(di)13.2(um)-238(bl)18.9(oc)15.1(ke)20.8(d)-251.2(s)0(t)17.7(a)0(t)18.5(e)-251.6(af)19.2(te)12.8(r)-247.1(a)0(m)17.7(i)0(l)16.5(o)0(r)19.6(i)0(d)13.2(e)0(\))-236.8(i)0(s)-244.1(s)0(h)20(o)0(w)17.3(n)-251.2(in)-237.2(fi)17.3(gu)15.5(re)]TJ T* [(3.)-445(The)-450.7(PD)-454.2(cha)-8.8(nges)-454.2(after)-454.1(UTP)-459.1(were)-453.2(short)-458.5(lasting)-457.9(with)]TJ 0 -1.0698 TD [(PD)-260.7(reverting)-260.3(to)-260(the)-255.5(value)-257.4(of)-259.2(the)-255.5(post)-257(amilori)-11.9(de)-252.3(PD)-255.1(wi)-7.8(thin)]TJ 0 -1.0755 TD [(30\261)-8(40)-542.1(min)-542.7(follow)-9.2(ing)-545.3(a)-541.8(single)-545.8(adminis)-9.1(tration)-549.4(of)-543.7(10.0)]TJ ET 1 i 309.316 749.367 228.019 -0.51 re f 309.316 704.523 228.019 -0.51 re f 309.316 640.743 228.019 -0.454 re f BT /F2 1 Tf 8.966 0 0 8.966 309.316 772.667 Tm [(Table)-338.2(1.)-330.4(\261)-333.2(Potential)-313.6(difference)-305.8(\(PD\))-308.4(changes)-305.5(in)-304.9(cystic)-308.3(fib-)]TJ 0 -1.0559 TD [(rosis)-502(\(CF\))-493.1(mice)-495.6(and)-500.1(control)-495.8(animals)-495.1(with)-494.5(the)-499.2(amiloride)]TJ T* [(uridine)-336.1(triphosphate)-333.5(\(UTP\))-339.3(combination)]TJ /F3 1 Tf 0 -1.7072 TD [(Mouse)-334.2(type)-3869.7(Basal)-334.1(PD)]TJ 9.7752 -1.0559 TD (mV)Tj /F8 1 Tf 5.6843 1.0559 TD (D)Tj /F3 1 Tf 0.6639 0 TD [(PD)-336(after)]TJ -1.6313 -1.0559 TD [(amiloride)-340.1(1.0)]TJ 0.999 -1.0559 TD (mmol)Tj /F11 1 Tf 2.3142 0.2213 TD (.)Tj /F3 1 Tf 0.2719 -0.2213 TD (L)Tj 6.725 0 0 5.977 476.787 723.458 Tm (-1)Tj 8.966 0 0 8.966 457.172 710.022 Tm (mV)Tj /F8 1 Tf 4.3628 3.1678 TD (D)Tj /F3 1 Tf 0.6639 0 TD [(PD)-336(after)]TJ -0.5185 -1.0559 TD [(UTP)-332.6(1.0)]TJ T* (mmol)Tj /F11 1 Tf 2.3079 0.2213 TD (.)Tj /F3 1 Tf 0.2719 -0.2213 TD (L)Tj 6.725 0 0 5.977 526.167 723.458 Tm (-1)Tj 8.966 0 0 8.966 506.551 710.022 Tm (mV)Tj -21.9974 -2.0044 TD [(MF1)-332.9(control)]TJ 0.6702 -1.0496 TD (n)Tj /F9 1 Tf 0.4995 0 TD (=)Tj /F3 1 Tf 0.5501 0 TD (6)Tj 4.9951 1.0496 TD [(-20)-334.6(\(-13\261)-170.1(-24\))-4912.8(7)-4893.4(-)0(5)]TJ -6.7149 -2.1055 TD [(CF)-337.4(insertional)]TJ 0.6702 -1.0559 TD (n)Tj /F9 1 Tf 0.4995 0 TD (=)Tj /F3 1 Tf 0.5501 0 TD (10)Tj 4.9951 1.0559 TD [(-28)-334.6(\(-20\261)-170.1(-36\)*)-3913.3(13*)-4291.7(-8)]TJ 6.725 0 0 5.977 518.74 677.14 Tm (#)Tj 8.966 0 0 8.966 309.316 654.236 Tm (CF)Tj /F8 1 Tf 1.5554 0 TD (D)Tj /F3 1 Tf 0.6639 0 TD (F508)Tj -1.5491 -1.0559 TD (n)Tj /F9 1 Tf 0.4995 0 TD (=)Tj /F3 1 Tf 0.5501 0 TD (7)Tj 4.9951 1.0559 TD [(-34)-334.6(\(-25\261)-170.1(-39\)*)]TJ 6.725 0 0 5.977 424.346 658.205 Tm (,)Tj 8.966 0 0 8.966 426.047 654.236 Tm [(**)-2711.5(17*)]TJ 6.725 0 0 5.977 472.762 658.205 Tm (,)Tj 8.966 0 0 8.966 474.463 654.236 Tm [(**)-2604(-15*)]TJ 6.725 0 0 5.977 523.105 658.205 Tm (,)Tj /F12 1 Tf 0.2529 0 TD ({)Tj /F3 1 Tf 8.966 0 0 8.966 309.316 627.307 Tm [(Data)-287.7(are)-283.5(presented)-290.1(as)-278.2(the)-285.2(median)-285.3(with)-284.2(the)-285.2(range)-288.8(in)-279.6(parentheses.)]TJ 0 -1.0559 TD [(*:)-564.1(p)]TJ /F9 1 Tf 1.8336 0 TD (<)Tj /F3 1 Tf 0.5564 0 TD (0.01;)Tj 6.725 0 0 5.977 353.877 621.864 Tm (#)Tj 8.966 0 0 8.966 357.279 617.839 Tm 0.5646 Tc (:p)Tj /F9 1 Tf 1.3341 0 TD 0 Tc (<)Tj /F3 1 Tf 0.5501 0 TD [(0.05,)-560.7(comparison)-569.9(between)-564.2(control)-564.7(and)-567.3(CF)]TJ -7.2334 -1.0559 TD [(groups.)-299.2(**:)-291.7(p)]TJ /F9 1 Tf 5.3176 0 TD (<)Tj /F3 1 Tf 0.5501 0 TD (0.05;)Tj /F12 1 Tf 6.725 0 0 5.977 382.677 612.397 Tm ({)Tj /F3 1 Tf 8.966 0 0 8.966 386.079 608.371 Tm 0.2927 Tc (:p)Tj /F9 1 Tf 1.0622 0 TD 0 Tc (<)Tj /F3 1 Tf 0.5564 0 TD [(0.01,)-288.8(comparison)-298(between)]TJ /F8 1 Tf 10.8059 0 TD (D)Tj /F3 1 Tf 0.6639 0 TD [(F508)-293.7(and)]TJ -21.6496 -1.0559 TD [(insertional)-340.7(CF)-331.1(groups.)]TJ ET 308.976 262.998 230.003 -0.51 re f 308.976 218.154 230.003 -0.51 re f 308.976 154.375 230.003 -0.454 re f BT /F2 1 Tf 8.966 0 0 8.966 308.976 286.299 Tm [(Table)-331.9(2.)-336.7(\261)-333.2(Potential)-294.6(difference)-286.8(\(PD\))-295.7(changes)-286.5(in)-292.2(cystic)-295.6(fib-)]TJ T* [(rosis)-337.6(\(CF\))-341.4(mice)-337.6(and)-335.7(control)-337.7(animals)-343.3(with)-336.5(the)-341.1(loperamide/)]TJ T* [(uridine)-336.1(triphosphate)-333.5(\(UTP\))-333(combination)]TJ /F3 1 Tf 0 -1.7072 TD [(Mouse)-334.2(type)-3616.8(Basal)-334.1(PD)]TJ 9.5223 -1.0559 TD (mV)Tj /F8 1 Tf 5.8108 1.0559 TD (D)Tj /F3 1 Tf 0.6639 0 TD [(PD)-336(after)]TJ -0.98 -1.0559 TD (loperamide)Tj -0.3288 -1.0559 TD [(1.0)-330.7(mmol)]TJ /F11 1 Tf 3.8949 0.2213 TD (.)Tj /F3 1 Tf 0.2719 -0.2213 TD (L)Tj 6.725 0 0 5.977 483.42 237.09 Tm (-1)Tj 8.966 0 0 8.966 455.584 223.654 Tm (mV)Tj /F8 1 Tf 4.7169 3.1678 TD (D)Tj /F3 1 Tf 0.6702 0 TD [(PD)-329.7(after)]TJ -0.5248 -1.0559 TD [(UTP)-332.6(1.0)]TJ T* (mmol)Tj /F11 1 Tf 2.3142 0.2213 TD (.)Tj /F3 1 Tf 0.2719 -0.2213 TD (L)Tj 6.725 0 0 5.977 527.754 237.09 Tm (-1)Tj 8.966 0 0 8.966 508.138 223.654 Tm (mV)Tj -22.2124 -2.0044 TD [(MF1)-332.9(control)]TJ 0.6639 -1.0559 TD (n)Tj /F9 1 Tf 0.4995 0 TD (=)Tj /F3 1 Tf 0.5564 0 TD (14)Tj 4.9635 1.0559 TD [(-22)-334.6(\(-12\261)-163.8(-27\))-5070.9(6)-5159(-)0(3)]TJ -6.6833 -2.1055 TD [(CF)-331.1(insertional)]TJ 0.6639 -1.0559 TD (n)Tj /F9 1 Tf 0.4995 0 TD (=)Tj /F3 1 Tf 0.5564 0 TD (14)Tj 4.9635 1.0559 TD [(-28.5)-330.6(\(-18\261)-170.1(-38\)*)-3401.1(15*)-3368.6(-12.5*)]TJ -6.6833 -2.1118 TD (CF)Tj /F8 1 Tf 1.5491 0 TD (D)Tj /F3 1 Tf 0.6702 0 TD (F508)Tj -1.5554 -1.0559 TD (n)Tj /F9 1 Tf 0.4995 0 TD (=)Tj /F3 1 Tf 0.5564 0 TD (3)Tj 4.9635 1.0559 TD [(-34)-334.6(\(-30\261)-163.8(-38\))-4571.4(16)-4576.8(-12)]TJ -6.6833 -3.0034 TD [(Data)-275.1(are)-277.2(presented)-277.5(as)-271.8(the)-272.5(median)-279(with)-271.6(the)-278.8(range)-269.9(in)-273.3(parentheses.)]TJ 0 -1.0559 TD [(*:)-469.3(p)]TJ /F9 1 Tf 1.7388 0 TD (<)Tj /F3 1 Tf 0.5501 0 TD [(0.01,)-465.9(comparison)-468.8(between)-469.3(control)-469.8(mice)-469.7(and)-466.2(insertional)]TJ -2.2889 -1.0559 TD [(mutant)-458.6(mice.)-453.6(Statistical)-456.7(significance)-463.9(was)-451.7(not)-456.1(assessed)-455.3(in)-456.6(the)]TJ /F8 1 Tf T* (D)Tj /F3 1 Tf 0.6639 0 TD [(F508)-338(group)-333.5(due)-333.4(to)-330.2(small)-333.9(numbers.)]TJ 23.2114 76.3934 TD (147)Tj 7.472 0 0 7.472 204.038 797.499 Tm 0.0001 Tc [(SODIUM)-335.6(CHANN)-12.6(EL)-332.1(BLOCKERS)-344.4(AND)-334.5(UTP)-333.8(IN)-340.8(CF)-329.7(MICE)]TJ ET endstream endobj 18 0 obj << /ProcSet [/PDF /Text ] /Font << /F2 5 0 R /F3 6 0 R /F4 7 0 R /F6 9 0 R /F8 11 0 R /F9 12 0 R /F11 19 0 R /F12 20 0 R >> /ExtGState << /GS2 14 0 R >> >> endobj 22 0 obj << /Length 32232 >> stream BT /F3 1 Tf 9.963 0 0 9.963 58.28 529.568 Tm 0 g /GS2 gs 0 Tc (mmol)Tj /F11 1 Tf 2.3161 0.1992 TD 0 Tw (.)Tj /F3 1 Tf 0.2731 -0.1992 TD (L)Tj 7.472 0 0 6.641 90.085 533.99 Tm (-1)Tj 9.963 0 0 9.963 99.383 529.568 Tm [(UTP)104.3(.)-313.4(The)-314.1(acti)-8.6(on)-308.8(o)-6.5(f)-309.7(UTP)-316.8(was)-315.1(also)-314.3(found)-318.4(to)-316.9(be)]TJ -4.1256 -1.0527 TD [(dose)-260.7(dependen)-7.3(t)-259.2(from)-259.8(a)-262.9(range)-262.3(of)-253.5(0.)-6.8(1\26110.0)-260.3(mmol)]TJ /F11 1 Tf 18.9211 0.2049 TD (.)Tj /F3 1 Tf 0.2731 -0.2049 TD (L)Tj 7.472 0 0 6.641 255.515 523.502 Tm (-1)Tj 9.963 0 0 9.963 264.246 519.08 Tm (\(n)Tj /F9 1 Tf 0.8194 0 TD (=)Tj /F3 1 Tf 0.5577 0 TD (3,)Tj -22.0509 -1.0471 TD [(fig.)-490.3(4\).)-492.9(Higher)-490.9(con)-8.4(centratio)-11.1(ns)-486.4(did)-488.4(not)-494.1(produce)-491.4(furt)-8.6(her)]TJ 0 -1.0528 TD [(incre)-8.6(ase)-334.3(in)-334(PD.)]TJ /F6 1 Tf 9.1675 -3.3859 TD [(Discuss)-9.1(ion)]TJ /F3 1 Tf -8.1659 -2.0998 TD [(Th)17.1(e)-371.1(b)0(a)15.1(s)0(a)19.6(l)-373(PD)-363.2(me)12(as)19.6(ur)19.6(em)12(en)20.8(ts)-363.6(in)-368.1(t)13.9(h)0(e)-366.1(t)0(w)14.9(o)-370.7(gr)19.6(ou)15.5(ps)-361.2(of)-367.3(C)11.6(F)]TJ -1.0015 -1.0528 TD [(mi)15.7(ce)-321(w)12.4(e)0(r)13.5(e)-325.5(si)17.7(gn)15.5(if)17.3(ic)18.4(an)20.8(tl)16.5(y)-330.8(g)0(r)19.6(e)0(a)14.7(t)13.9(er)-322.2(th)18.9(an)-320.6(th)18.9(e)-325.5(c)0(o)15.1(n)0(t)18.9(r)0(o)19.6(l)0(s)-323.8(s)0(u)20(g)0(g)21.2(e)0(s)13.9(t)0(-)]TJ 0 -1.0471 TD [(in)18.9(g)-427.6(a)0(n)-423(i)0(o)18.9(n)-427.6(tr)17.3(an)15.1(sp)20(or)13.9(t)-429.9(a)0(b)20.8(n)0(o)15.5(r)0(m)16.5(a)0(l)18.4(i)0(t)16.5(y)-427.6(si)17.7(mi)15.7(la)18.4(r)-429.2(t)0(o)-419.3(t)0(h)13.2(a)0(t)-419.7(s)0(e)19.6(e)0(n)-423(i)0(n)]TJ 0 -1.0528 TD [(hu)15.5(ma)17.7(ns)20(.)-461.3(T)0(h)17.1(e)]TJ /F8 1 Tf 5.7361 0 TD (D)Tj /F3 1 Tf 0.6601 0 TD [(F5)16.3(08)-451.1(mi)15.7(ce)-457.6(ha)20.8(d)-461.7(h)0(i)13.2(g)0(h)21.2(e)0(r)-453.1(n)0(a)15.1(s)0(a)19.6(l)-464.1(PD)-454.2(at)-453.9(re)13.5(st)]TJ -6.3962 -1.0471 TD [(co)15.1(mp)18.1(ar)19.2(ed)-269.4(to)-271.4(in)18.9(se)13.9(rt)17.3(io)18.9(na)20.8(l)-282(C)0(F)-272.9(m)0(i)15.7(c)0(e)-269.8(i)0(n)18.9(d)0(i)18.9(c)0(a)14.7(t)0(i)22.2(n)0(g)-274.7(a)-274.3(mo)12.4(re)-271(se)19.6(ve)15.1(re)]TJ 0 -1.0528 TD [(ph)15.5(en)20.8(ot)18.9(yp)15.5(e.)-200.7(P)11.4(r)0(e)13.5(v)0(i)18.9(o)0(u)21.2(s)-212.5(st)17.7(ud)15.5(i)13.9(e)0(s)-202.3(i)0(n)-203.1(b)0(o)21.2(t)0(h)-203.1(h)0(u)15.5(m)0(a)17.7(n)0(s)-201.9(a)0(n)20.8(d)-211.3(mi)15.7(ce)-201.5(ha)20.8(ve)]TJ 0 -1.0471 TD [(de)15.1(mo)18.1(ns)20(tr)17.3(at)18.4(ed)-343.4(a)-348.3(f)0(a)19.2(l)0(l)-342(i)0(n)-339.7(n)0(a)15.1(s)0(a)19.6(l)-350.3(ep)15.1(it)16.5(he)20.8(li)16.5(al)-340.1(PD)-340.4(af)13.5(te)18.4(r)-349.5(a)0(m)17.7(i)0(l)16.5(o)0(r)19.6(i)0(d)13.2(e)]TJ 0 -1.0528 TD [(ad)15.1(mi)21.4(ni)13.2(st)17.7(ra)19.2(ti)16.5(on)-496.6([1)13.9(0,)-507.6(17].)-516.4(The)-524.7(expected)-522.3(fall)-522(in)-521.8(PD)-516.8(was)]TJ 0 -1.0471 TD [(observ)-7.8(ed)-286.5(in)-282.7(all)-286.3(groups)-291.9(after)-289(adminis)-9.1(tration)-287.6(of)-287.7(the)-283.9(sodiu)-7.4(m)]TJ 0 -1.0528 TD [(channel)-350.4(blockin)-10.5(g)-342.2(agent)-348.4(amiloride.)-350(Simi)-10.2(lar)-342.4(chan)-9.6(ges)-345.3(have)]TJ 25.1977 17.7887 TD [(bee)-8.8(n)-438.9(show)-8.2(n)-438.9(with)-449.9(loperami)-10.7(de)-440.1(in)]TJ /F4 1 Tf 13.6915 0 TD [(in)-442.1(vitr)24.7(o)]TJ /F3 1 Tf 3.4883 0 TD [(studi)-9.8(es)-441.3(in)-442.1(the)]TJ -17.1798 -1.0641 TD [(bowe)-7.4(l)-242.1([18].)-245.6(It)-244.5(has)-242.9(previ)-8.2(ously)-246.4(been)-242.9(show)-8.2(n)-239.8(that)-247.2(loper)-8.2(amide)]TJ T* [(is)-460.3(effective)-454.6(on)-456.8(the)-460.3(CF)-460.7(mouse)-458.1(respi)-9.4(ratory)-460.1(mucos)-8.6(a)-456.4(a)0(s)-458.4(a)]TJ T* [(sodiu)-7.4(m)-328.3(channel)-333.3(blocker)-328.8(\(change)-332.5(in)]TJ /F8 1 Tf 14.5337 0 TD (D)Tj /F3 1 Tf 0.6658 0 TD [(PD)-329(-14)-328.2(mV)]TJ /F4 1 Tf 5.0646 0 TD (versus)Tj /F3 1 Tf -20.264 -1.0698 TD [(ami)-8.2(loride)-244.6(-)-241.4(1)0(5)-240.5(m)0(V)-8.6(\))-241.4(and)-241.7(had)-241.7(a)-240.2(longer)-248(durat)-8.2(ion)-243.7(of)-242.1(action)-243.5(\(8)]TJ 0 -1.0641 TD (h)Tj /F4 1 Tf 0.9162 0 TD (versus)Tj /F3 1 Tf 2.9477 0 TD [(ami)-8.2(loride)-421.1(4)-410.5(h)0(\))-418.5([14].)-416.3(It)-415.2(has)-413.6(a)-416.6(relativel)-13.5(y)-410.5(longer)]TJ -3.8639 -1.0641 TD [(durat)-8.2(ion)-545.3(of)-543.7(acti)-8.6(on)-542.1(when)-548(adminis)-9.2(tered)-549.2(systemi)-10.3(cally)-544.3(in)]TJ T* [(human)-7.4(s)-508.4(\(time)-514.5(\()]TJ /F4 1 Tf 6.5157 0 TD (t)Tj /F3 1 Tf 0.2675 0 TD [(\)0.5)-510.7(hours)]TJ /F9 1 Tf 4.8028 0 TD (=)Tj /F3 1 Tf 0.552 0 TD [(1)27.7(1)-501.5(h\))-509.6(when)-513.8(compa)-7.8(red)-505.1(to)]TJ -12.1379 -1.0641 TD [(ami)-8.2(loride)-449.5(\()]TJ /F4 1 Tf 4.5581 0 TD (t)Tj /F3 1 Tf 0.2731 0 TD (0.5)Tj /F9 1 Tf 1.2519 0 TD (=)Tj /F3 1 Tf 0.552 0 TD [(6)-444.6(h)-6.5(\))-446.2([19])-450.1(suggestin)-8.7(g)-444.6(that)-452.1(less)-446.4(freque)-8.6(nt)]TJ -6.6352 -1.0698 TD [(admi)-9(nistration)-378.8(would)-368.6(achiev)-8.2(e)-365.4(sufficient)-367.1(sodium)-369.8(channel)]TJ 0 -1.0641 TD [(blocka)-7.8(de.)-406.3(A)-397.4(fall)-408.1(in)-402.3(PD)-403(was)-400.5(seen)-409.1(with)-404.4(loperami)-10.7(de)-400.3(con-)]TJ T* [(siste)-11.4(nt)-436.4(with)-438.5(Na)]TJ 7.472 0 0 6.641 372.246 414.255 Tm (+)Tj 9.963 0 0 9.963 380.806 409.833 Tm [(blocka)-7.8(de.)-434.8(The)-439.3(subseq)-7.4(uent)-438.3(addition)-440.4(of)]TJ -7.1758 -1.0641 TD [(UTP)-612.8(\(0.1\26110)-615.4(mm)-7.8(ol)]TJ /F11 1 Tf 8.4903 0.1992 TD (.)Tj /F3 1 Tf 0.2731 -0.1992 TD (L)Tj 7.472 0 0 6.641 402.633 403.653 Tm (-1)Tj 9.963 0 0 9.963 408.813 399.231 Tm [(\))-611.2(dissolved)-617.6(in)-607.1(a)-610.1(chlor)-8.2(ide-free)]TJ -9.9869 -1.0698 TD [(veh)-8.4(icle)-441.1(incre)-8.6(ased)-443.2(the)-443.3(PD)-442.8(in)-442.1(all)-439.9(groups)-445.5(sugges)-7.4(ting)-446(that)]TJ 0 -1.0641 TD (Ca)Tj 7.472 0 0 6.641 320.372 382.394 Tm (2+)Tj 9.963 0 0 9.963 331.653 377.972 Tm [(activated)-340(Cl)]TJ 7.472 0 0 6.641 379.842 382.394 Tm (-)Tj 9.963 0 0 9.963 385.568 377.972 Tm [(secret)-11(ion)-334.7(was)-337.9(occurr)-8.6(ing.)]TJ -6.6523 -1.0471 TD [(Th)17.1(e)-211.7(r)0(e)19.2(s)0(t)17.7(i)0(n)18.8(g)-211.3(ch)20.8(lo)13.2(ri)17.3(de)-195.4(co)15.1(nd)21.2(uc)15.1(ta)18.4(nc)15.1(e)-206(o)0(f)-202.3(t)0(h)18.9(e)-206(na)15.1(sa)19.6(l)-208(e)0(p)15.1(i)0(t)16.5(h)0(e)20.8(l)0(i)16.5(u)0(m)]TJ -1.0015 -1.0641 TD [(is)-528.6(re)19.2(fl)17.3(ec)14.7(t)13.9(e)0(d)-525.5(b)0(y)-525.1(a)-530.4(sm)16.9(al)18.5(l)-532.4(i)0(n)13.2(c)0(r)19.2(e)0(a)14.7(s)0(e)-521(i)0(n)-521.8(n)0(e)15.1(g)0(a)15.1(t)13.9(iv)13.2(e)-530.4(n)0(a)15.1(s)0(a)19.6(l)-532.4(P)11.4(D)]TJ ET 0 0 0 1 K 0 J 0 j 0.5 w 3.864 M []0 d /GS3 gs 1 i 92.78 770.88 m 92.78 645.381 l 92.78 645.551 m 281.779 645.551 l 92.78 645.598 m 89.28 645.598 l 92.775 663.086 m 89.275 663.086 l 92.78 680.961 m 89.28 680.961 l 92.785 698.836 m 89.285 698.836 l 92.79 716.711 m 89.29 716.711 l 92.794 734.586 m 89.294 734.586 l 92.799 752.914 m 89.299 752.914 l 92.804 770.562 m 89.304 770.562 l S BT /F17 1 Tf 10 0 0 10 74.622 767.487 Tm 0 0 0 1 k /GS4 gs -0.0048 Tc (-35)Tj -0.0342 -1.7821 TD 0 Tc (-30)Tj 0.0307 -1.8523 TD -0.011 Tc (-25)Tj -0.0399 -1.7814 TD 0 Tc (-20)Tj 0.0325 -1.8137 TD -0.0173 Tc (-15)Tj -0.0234 -1.8062 TD 0 Tc (-10)Tj 0.442 -1.7184 TD (-5)Tj 0.2443 -1.7316 TD (0)Tj ET /GS3 gs 92.78 645.756 m 92.78 642.756 l 139.28 645.586 m 139.28 642.586 l 186.94 645.558 m 186.94 642.558 l 234.6 645.53 m 234.6 642.53 l 281.496 645.586 m 281.496 642.586 l S BT 10 0 0 10 90.155 631.381 Tm /GS4 gs [(0)-4269(5)-4031.5(10)-3838(15)-3775.5(20)]TJ 8.1 -1.8125 TD [(T)18(ime min)]TJ 0 10 -10 0 66.905 694.881 Tm (PD mV)Tj ET 3.864 M /GS3 gs 109.655 774.005 m 109.655 778.255 l S 109.655 774.297 m 111.405 774.297 l 109.655 769.922 l 107.905 774.297 l 109.655 774.297 l f* 144.53 774.255 m 144.53 778.13 l S 144.53 774.547 m 146.28 774.547 l 144.53 770.172 l 142.78 774.547 l 144.53 774.547 l f* 198.529 774.005 m 198.529 778.255 l S 198.529 774.297 m 200.28 774.297 l 198.529 769.922 l 196.779 774.297 l 198.529 774.297 l f* BT 10 0 0 10 202.53 770.256 Tm /GS4 gs -0.0199 Tc (UTP)Tj -5.4625 0 TD 0 Tc (Amiloride)Tj -3.5375 0.0189 TD (Basal)Tj ET [4 4 ]0 d /GS3 gs 92.655 688.631 m 94.53 688.881 l 95.905 689.006 l 97.78 690.381 l 99.655 691.631 l 101.655 693.631 l 104.53 696.256 l 106.155 697.631 l 108.155 697.756 l 110.155 697.256 l 112.155 696.756 l 115.155 696.256 l 117.905 695.506 l 120.03 694.756 l 122.53 694.381 l 125.03 694.131 l 127.28 694.631 l 129.28 694.881 l 131.405 694.881 l 134.405 693.881 l 136.655 692.881 l 138.28 691.006 l 140.155 688.506 l 142.53 685.506 l 144.155 680.756 l 145.655 676.631 l 147.03 672.881 l 149.53 668.631 l 151.53 665.631 l 154.405 664.006 l 158.28 663.756 158.53 663.756 v 158.78 663.756 161.905 664.256 y 165.405 664.881 l 169.655 665.256 l 174.155 665.881 l 178.03 666.381 l 181.655 666.256 l 185.155 666.131 l 189.53 666.506 l 192.78 668.006 l 194.78 670.381 l 196.404 673.506 l 196.905 677.256 l 197.28 684.006 l 197.529 689.006 197.655 689.256 v 197.779 689.506 198.654 692.256 y 200.529 694.881 l 202.654 696.381 l 205.279 697.256 l 208.779 698.381 209.029 698.131 v 209.279 697.881 213.279 697.506 y 218.279 695.756 l 221.279 694.006 l 224.654 692.381 l 229.529 690.506 l 234.779 688.381 l 238.654 687.256 l 244.654 686.631 l 249.654 686.256 l 255.154 686.131 l 261.404 686.756 l S []0 d 92.655 747.381 m 94.78 748.756 l 96.28 749.631 l 97.905 750.381 l 99.905 751.131 l 102.28 751.63 l 104.53 751.881 l 107.155 751.756 l 110.155 751.381 l 112.53 750.88 l 115.655 749.755 l 117.905 748.255 l 119.78 746.506 l 121.155 745.006 121.405 745.006 v 121.655 745.006 123.405 743.755 y 125.78 742.756 l 128.155 742.506 l 130.03 743.005 l 132.405 743.631 l 134.655 744.381 l 136.905 744.256 l 138.905 743.38 l 140.78 742.881 l 143.155 742.63 l 144.03 741.88 l 144.28 740.006 l 144.78 736.756 l 145.405 731.756 l 145.655 727.006 l 145.78 722.506 l 146.03 718.881 l 146.155 713.381 l 146.53 706.006 l 146.655 702.256 l 146.905 697.381 l 147.53 690.631 l 148.405 682.881 l 148.53 679.381 l 149.28 676.756 l 150.03 675.381 l 150.78 674.381 151.03 674.381 v 151.28 674.381 152.53 674.006 152.78 673.881 c 153.03 673.756 155.155 673.881 y 157.28 674.256 l 159.78 674.756 l 161.78 674.756 l 163.28 674.631 l 164.78 674.381 l 166.53 673.631 l 168.155 673.006 l 169.905 672.506 l 171.905 672.381 172.155 672.256 v 172.405 672.131 174.905 671.381 y 178.155 671.006 l 182.405 670.506 l 186.155 670.006 l 189.53 669.381 l 192.78 669.131 l 196.029 669.381 l 197.404 670.381 l 199.029 671.631 l 201.405 674.006 l 202.404 676.256 l 202.905 679.506 l 203.529 684.006 l 204.404 690.756 l 205.279 696.006 l 207.029 702.381 l 209.404 707.006 l 212.279 710.006 l 214.654 711.506 l 218.029 713.256 l 222.029 715.006 l 226.654 716.006 l 230.029 716.381 l 234.029 716.506 l 236.779 716.256 l 238.779 715.506 l 241.279 715.256 l 243.404 715.631 l 246.029 716.006 l 247.904 716.006 l 250.154 715.256 l 251.029 714.506 l 253.779 714.756 l 256.154 714.631 l 257.779 714.131 l 259.904 712.506 l 262.154 711.756 l S BT /F3 1 Tf 7.97 0 0 7.97 58.28 599.584 Tm 0 g /GS2 gs [(Fig.)-327.1(1.)-665.5(\261)-922.6(Example)-451(of)-458.3(nasal)-460.5(potentia)11.7(l)-462.7(diff)12.8(erence)-460.1(\(PD\))-454.6(changes)-452.9(in)-460.6(a)]TJ /F4 1 Tf 0 -1.0599 TD (cftr)Tj /F3 1 Tf 5.977 0 0 5.313 69.109 594.652 Tm -0.0001 Tc (tm1HGU)Tj 7.97 0 0 7.97 92.353 591.137 Tm 0 Tc [(cystic)-140.7(fibrosis)-140.1(\(CF\))-143.8(mouse)-139.3(\(\261\261\261\261\))-144.2(and)-142.1(a)-139.2(matched)-141.4(control)-138.6(\(\261)-145.4(\261)-147.3(\261)-140.2(\))]TJ -4.275 -1.067 TD [(with)-326.1(the)-322.3(amilorid)10.2(e)-324.1(uridine)-323.5(triphosphate)-315.6(\(UTP\))-320(combination)10.6(.)-326.2(The)-322.6(PD)-323.3(is)]TJ 0 -1.0599 TD [(shown)-206.6(at)-210.6(the)-208.5(resting)-203.8(state,)-212.9(followed)-203(by)-209.2(application)-203.9(of)-209.4(amiloride)-207.2(causing)-200.2(a)]TJ T* [(fall)-173.4(in)-176(PD)-181.1(which)-171.2(is)-177.2(more)-168.9(marked)-170.8(in)-176(the)-180(CF)-169(mouse.)-173.8(Subsequent)-163.2(application)]TJ 0 -1.067 TD [(of)-209.4(UTP)-203(increases)-202.5(the)-208.5(PD)-209.5(and)-206.1(the)-201.4(CF)-211.7(mouse)-203.3(again)-203.2(shows)-200.7(greater)-205.5(changes.)]TJ ET 3.864 M /GS3 gs 93.045 326.471 m 93.045 200.972 l 93.045 201.142 m 282.044 201.142 l 93.045 201.189 m 89.545 201.189 l 93.04 218.677 m 89.54 218.677 l 93.045 236.552 m 89.545 236.552 l 93.049 254.427 m 89.549 254.427 l 93.054 272.302 m 89.554 272.302 l 93.059 290.177 m 89.559 290.177 l 93.064 308.505 m 89.564 308.505 l 93.068 326.153 m 89.568 326.153 l S BT /F17 1 Tf 10 0 0 10 74.887 323.078 Tm 0 0 0 1 k /GS4 gs -0.0048 Tc (-35)Tj -0.0342 -1.7821 TD 0 Tc (-30)Tj 0.0307 -1.8523 TD -0.011 Tc (-25)Tj -0.0399 -1.7814 TD 0 Tc (-20)Tj 0.0325 -1.8137 TD -0.0173 Tc (-15)Tj -0.0234 -1.8061 TD 0 Tc (-10)Tj 0.442 -1.7184 TD (-5)Tj 0.2443 -1.7316 TD (0)Tj ET /GS3 gs 93.045 201.347 m 93.045 198.347 l 139.544 201.177 m 139.544 198.177 l 187.205 201.149 m 187.205 198.149 l 234.865 201.121 m 234.865 198.121 l 281.761 201.177 m 281.761 198.177 l S BT 10 0 0 10 90.42 186.972 Tm /GS4 gs [(0)-4269(5)-4031.5(10)-3838(15)-3775.5(20)]TJ 8.1 -1.8125 TD [(T)18(ime min)]TJ 0 10 -10 0 67.17 250.472 Tm (PD mV)Tj ET 3.864 M /GS3 gs 109.92 329.596 m 109.92 333.847 l S 109.92 329.888 m 111.67 329.888 l 109.92 325.513 l 108.17 329.888 l 109.92 329.888 l f* 144.794 329.846 m 144.794 333.721 l S 144.794 330.138 m 146.544 330.138 l 144.794 325.763 l 143.044 330.138 l 144.794 330.138 l f* 198.794 329.596 m 198.794 333.847 l S 198.794 329.888 m 200.544 329.888 l 198.794 325.513 l 197.044 329.888 l 198.794 329.888 l f* BT 10 0 0 10 202.794 325.847 Tm /GS4 gs -0.0199 Tc (UTP)Tj -5.4625 0 TD 0 Tc (Loperamide)Tj -3.5375 0.0188 TD (Basal)Tj ET 3.864 M /GS3 gs 93.059 290.177 m 94.28 290.625 l 95.03 292 l 96.155 294.75 l 96.905 296.75 l 97.53 297.625 l 98.53 298 l 99.405 298.5 l 100.28 300.375 l 101.155 302.5 l 101.905 304.75 l 103.155 306.75 l 105.03 307.875 l 106.905 308.25 l 108.655 307.75 l 109.405 307.75 l 110.78 308.375 l 112.655 309.375 l 114.03 309.625 114.28 309.5 v 114.53 309.375 115.78 308.875 y 116.655 308.875 l 118.28 310.125 l 120.03 310.625 l 122.28 310.125 122.405 309.875 v 122.53 309.625 123.53 309 123.905 308.75 c 124.28 308.5 125.655 308.125 y 128.28 308.5 l 130.405 309.25 l 132.405 309.25 l 135.03 308.5 l 136.655 306.875 l 138.155 303.875 l 138.655 302.125 l 138.905 298.125 l 139.405 292.25 l 139.405 288 l 139.53 283.375 l 139.405 279.125 l 139.405 274.875 l 139.655 268.75 l 140.155 265.125 l 140.53 261.375 l 140.905 259 l 141.53 256.125 l 142.28 254.25 l 143.405 253.25 l 144.905 252.875 l 146.405 253.125 l 148.28 253 l 149.655 252.5 l 152.28 251.75 l 155.78 251 l 161.405 250.875 l 167.53 250.375 l 171.28 250.375 l 174.78 251 l 178.03 251.75 l 182.03 251.875 l 185.03 252.875 l 187.905 253.75 l 190.28 254.625 l 192.78 256.375 l 193.78 258.875 l 196.53 269 l 198.405 276.625 l 200.53 289.75 l 202.53 300 l 203.53 305.5 l 204.654 309.125 l 205.905 312.125 l 207.279 314.75 l 208.905 316.375 l 211.029 317.75 l 212.28 317.5 l 214.029 317.125 l 215.779 316.625 l 217.155 316.5 217.404 316.5 v 217.654 316.5 219.03 316.625 y 220.53 315.5 l 221.655 314.75 l 223.654 314.125 l 225.154 313.625 l 227.28 312.375 l 229.404 311.25 l 231.404 311 l 233.279 311.875 l 235.404 312.625 l 237.404 313.375 237.654 313.25 v 237.904 313.125 240.529 313.75 y 243.404 313.375 l 245.779 312.5 246.029 312.5 v 246.279 312.5 248.279 312.625 y 250.779 313.25 l 253.154 313.75 l 257.154 313.5 l S 3.864 M [4 4 ]0 d 93.03 284.25 m 95.155 285.125 l 96.655 285.875 l 99.03 286.875 l 101.28 287.75 l 103.905 288.25 l 106.405 288.375 l 109.155 287.625 l 112.28 287 l 114.655 286.375 l 116.905 286.375 l 120.155 286.875 l 122.905 287.875 l 124.78 287.875 l 127.53 287.25 l 129.655 286.75 l 131.905 286.5 l 134.78 286.125 l 136.78 285.125 l 138.53 284 l 140.28 281.375 l 140.905 278.5 l 141.53 272.75 l 141.655 270.125 l 141.905 266 l 142.03 264 l 142.655 261.625 l 143.155 259.75 l 144.03 258.5 l 145.155 257.875 l 147.405 257.375 147.905 257.5 v 148.405 257.625 149.655 258 y 152.155 258.125 l 157.155 258.5 l 162.655 259.25 l 168.155 259.875 l 172.905 260.375 l 177.78 260.375 l 183.155 260.5 l 188.53 260.75 l 192.53 260.5 l 194.78 260.875 l 196.28 261.75 l 197.53 263 l 200.155 268.25 l 201.78 270.125 l 205.029 271.875 l 207.155 272.625 l 209.154 273.125 l 211.905 273.125 l 214.405 272.5 l 217.279 271.75 l 220.654 270.75 l 224.404 270.5 l 227.28 271.375 227.904 271.125 v 228.529 270.875 233.654 272.25 y 238.904 273 l 244.154 273.125 l 247.779 273.5 l 253.279 273.375 l 255.654 273.25 l S BT /F3 1 Tf 7.97 0 0 7.97 58.28 154.885 Tm 0 g /GS2 gs [(Fig.)-327.1(2.)-331.2(\261)-332.2(Nasal)-256.7(potential)-258.9(dif)18(ference)-259(\(PD\))-262.5(changes)-253.7(in)-261.4(a)]TJ /F4 1 Tf 21.6097 0 TD (cftrtm)Tj /F3 1 Tf 5.977 0 0 5.313 249.222 158.4 Tm -0.0001 Tc (1HGU)Tj 7.97 0 0 7.97 267.137 154.885 Tm 0 Tc (cystic)Tj -26.2048 -1.067 TD [(fibrosis)-481.5(\(CF\))-485.3(mouse)-487.9(\(\261\261\261\))-480.6(and)-483.5(a)-487.7(matched)-482.8(control)-480(\(\261)-486.8(\261)-488.7(\261)0(\))-486.8(with)-482.6(the)]TJ 0 -1.0599 TD [(loperamide)-208.8(uridine)-202.6(triphosphate)-208.9(\(UTP\))-206.2(combination)10.6(.)-212.4(The)-208.8(PD)-209.5(is)-212.8(shown)-206.6(at)]TJ 0 -1.067 TD [(the)-258.3(resting)-260.7(state,)-262.7(followed)-252.8(by)-266.1(application)-253.7(of)-259.2(loperamide)-258.6(causing)-257.1(a)-260.1(fall)-265.8(in)]TJ 0 -1.0599 TD [(PD)-302(which)-306.3(is)-305.3(more)-304(marked)-298.8(in)-304.1(the)-308.1(CF)-304.2(mouse.)-294.8(Subsequent)-298.4(application)-296.3(of)]TJ T* [(UTP)-295.4(increases)-302.1(the)-300.9(PD)-294.9(and)-305.7(the)-300.9(CF)-297.1(mouse)-295.8(again)-302.8(shows)-293.1(greater)-298(changes.)]TJ ET 3.864 M []0 d /GS3 gs 341.93 774.38 m 341.93 647.381 l 341.93 647.523 m 390.429 647.523 l 393.179 647.551 m 528.929 647.551 l 388.278 645.381 m 392.403 649.506 l 390.995 645.261 m 395.12 649.386 l 341.93 647.558 m 339.43 647.558 l 341.93 663.881 m 339.43 663.881 l 341.93 680.256 m 339.43 680.256 l 341.93 695.952 m 339.43 695.952 l 341.93 711.647 m 339.43 711.647 l 341.93 726.947 m 339.43 726.947 l 341.93 742.246 m 339.43 742.246 l 341.93 757.545 m 339.43 757.545 l 341.93 774.062 m 339.43 774.062 l 341.93 647.756 m 341.93 645.006 l 367.805 647.506 m 367.805 644.756 l 394.929 647.614 m 394.929 644.865 l 421.63 647.667 m 421.63 644.917 l 448.698 647.605 m 448.698 644.855 l 475.936 647.544 m 475.936 644.794 l 502.636 647.567 m 502.636 644.817 l 528.657 647.591 m 528.657 644.841 l S BT /F17 1 Tf 10 0 0 10 523.929 634.631 Tm 0 0 0 1 k /GS4 gs (60)Tj -2.6375 0 TD (50)Tj -2.6375 0 TD (40)Tj -2.737 0 TD (30)Tj -2.6833 0 TD (20)Tj -2.6858 0 TD (10)Tj -2.4564 0 TD (5)Tj -2.6038 0 TD (0)Tj -0.7087 0.9571 TD (0)Tj -0.2403 1.6802 TD (-5)Tj -0.4552 1.5877 TD (-10)Tj 0.0335 1.5934 TD -0.011 Tc (-15)Tj -0.0356 1.5691 TD 0 Tc (-20)Tj 0.0413 1.5243 TD -0.011 Tc (-25)Tj -0.0356 1.5205 TD 0 Tc (-30)Tj 0.0335 1.5703 TD -0.011 Tc (-35)Tj -0.0415 1.6288 TD -0.0048 Tc (-40)Tj 0 10 -10 0 318.43 699.381 Tm 0 Tc (PD mV)Tj 10 0 0 10 416.554 616.006 Tm [(T)18(ime min)]TJ ET /GS3 gs 341.93 726.947 m 343.055 726.881 l 344.93 727.506 l 346.93 727.881 l 348.805 728.631 l 350.93 729.881 l 351.93 730.631 l 352.93 731.131 l 353.68 731.756 l 354.68 731.381 l 355.93 730.756 l 357.055 729.881 357.305 729.756 v 357.555 729.631 357.555 729.131 357.805 728.881 c 358.055 728.631 358.555 727.881 y 359.055 726.756 l 359.43 725.756 l 360.18 724.506 l 361.43 724.381 l 362.43 723.881 l 363.18 723.256 l 363.68 722.381 l 364.055 720.881 l 364.805 720.006 l 365.93 719.881 l 366.555 717.131 l 367.055 711.631 l 367.055 708.006 l 366.93 704.131 l 367.305 700.131 l 367.68 697.256 l 367.93 695.506 l 368.554 693.881 l 368.68 692.756 368.929 692.631 v 369.18 692.506 370.305 691.756 y 372.055 692.006 l 373.305 693.006 l 375.555 693.756 l 377.68 693.506 l 379.679 693.131 l 381.43 691.881 l 382.555 689.381 382.804 689.131 v 383.054 688.881 383.929 687.881 384.054 687.631 c 384.179 687.381 384.679 686.256 384.929 686.131 c 385.179 686.006 385.804 685.756 386.054 686.006 c 386.304 686.256 386.929 687.006 387.429 687.006 c 387.929 687.006 388.804 687.881 y 389.679 689.881 l 390.179 693.256 l 390.429 703.756 l 390.179 710.881 l 390.179 719.506 l 389.929 728.006 l 390.304 733.256 l 390.804 737.506 l 391.179 739.131 l 391.054 742.131 l 391.554 744.505 m 391.929 746.38 l 392.179 748.255 l 393.179 749.38 l 394.179 749.005 l 394.929 748.006 l 395.554 746.881 l 397.054 746.256 l 398.429 745.881 l 399.429 746.005 l 400.179 747.13 l 401.179 748.255 l 402.304 748.381 l 403.179 747.631 l 404.054 746.631 l 405.179 747.13 l 406.429 748.506 l 407.179 749.38 l 408.179 749.631 l 408.179 749.631 m 408.679 750.006 l 409.679 749.88 409.679 749.631 v 409.679 749.38 410.554 749.13 y 411.929 749.005 l 413.179 748.881 l 414.554 748.63 l 416.554 747.631 l 417.554 746.755 l 418.554 745.381 l 419.054 743.881 l 419.554 742.131 l 420.554 740.38 l 420.804 738.631 l 421.429 735.381 l 422.304 733.256 l 423.054 731.631 l 423.804 730.506 l 426.304 730.131 l 427.804 730.381 l 429.679 730.881 l 431.804 731.006 l 433.429 730.631 l 435.804 729.256 l 438.304 727.506 l 440.679 725.506 l 442.054 723.756 l 443.429 722.131 l 445.929 722.256 l 446.679 722.381 l 448.304 721.381 l 449.554 718.756 l 450.179 715.881 l 451.429 713.631 l 452.804 711.631 l 454.554 710.381 l 456.429 709.756 l 458.554 709.506 l 459.679 709.631 l 461.679 710.006 l 462.554 709.631 l 463.929 709.006 l 464.929 708.381 l 465.554 709.131 l 466.679 709.131 l 467.679 708.381 l 468.804 707.881 l 470.554 707.881 l 471.804 707.131 l 472.554 706.506 l 473.804 707.131 l 474.804 706.881 l 476.179 705.756 l 477.179 702.756 l 478.304 697.881 l 478.679 695.381 l 479.554 694.756 l 480.554 694.256 l 481.929 693.256 l 481.929 692.256 l 483.304 691.131 l 485.054 690.756 l 486.179 690.381 l 487.429 689.756 l 489.804 688.381 l 491.804 687.756 l 494.304 687.881 l 497.179 687.631 l 499.179 687.381 l 501.054 686.756 l 502.054 683.881 l 502.554 681.881 l 503.304 680.131 l 504.304 679.381 l 505.554 679.381 l 506.179 680.131 l 507.304 679.506 l 508.054 678.756 l 509.304 678.881 l S 389.304 743.324 m 393.054 744.949 l 389.304 741.756 m 392.929 743.131 l S 3.864 M 353.055 767.818 m 353.055 770.443 l S 353.055 768.109 m 354.805 768.109 l 353.055 763.735 l 351.305 768.109 l 353.055 768.109 l f* 377.804 767.443 m 377.804 770.068 l S 377.804 767.734 m 379.555 767.734 l 377.804 763.36 l 376.054 767.734 l 377.804 767.734 l f* 416.617 767.818 m 416.617 770.443 l S 416.617 768.109 m 418.367 768.109 l 416.617 763.735 l 414.867 768.109 l 416.617 768.109 l f* BT 10 0 0 10 354.827 764.094 Tm /GS4 gs (Basal)Tj 2.4353 0.0411 TD (Amiloride)Tj 3.954 -0.0056 TD (UTP)Tj /F3 1 Tf 7.97 0 0 7.97 309.316 601.568 Tm 0 g /GS2 gs [(Fig.)-334.3(3.)-324.1(\261)-332.2(Duration)-259.9(of)-266.3(action)-267.6(of)-266.3(a)-260.1(single)-262.6(dose)-269.2(of)-259.2(cystic)-268.7(fibrosis)-261(\(UTP\))-263.1(10)]TJ 0 -1.0599 TD (mmol)Tj /F11 1 Tf 2.3118 0.249 TD (.)Tj /F3 1 Tf 0.2703 -0.249 TD (L)Tj 5.977 0 0 5.313 334.658 596.636 Tm (-1)Tj 7.97 0 0 7.97 343.332 593.121 Tm [(in)-467.7(a)]TJ /F4 1 Tf 2.1482 0 TD (cftrtm)Tj /F3 1 Tf 5.977 0 0 5.313 379.162 596.636 Tm -0.0001 Tc (1HGU)Tj 7.97 0 0 7.97 398.778 593.121 Tm 0 Tc [(cystic)-467.9(fibrosis)-460.2(\(CF\))-471(mouse.)-465.5(The)-464.8(potential)]TJ -11.2245 -1.067 TD [(differ)10.7(ence)-273.1(\(PD\))-269.6(is)-276.8(shown)-263.5(at)-274.6(the)-272.5(resting)-275(state,)-269.8(followed)-267(by)-273.2(application)-267.9(of)]TJ 0 -1.0599 TD [(amiloride)-385(causing)-385.2(a)-381(fall)-393.9(in)-382.3(PD.)-386.3(Subsequentl)14.3(y)59(,)-383.1(the)-386.3(application)-381.7(of)-387.2(UTP)]TJ T* [(increases)-209.6(the)-208.5(PD)-209.5(which)-206.8(declines)-199.5(with)-212.3(time)-209(reaching)-203.2(the)-208.5(value)-210.4(of)-209.4(the)-208.5(post-)]TJ 0 -1.067 TD [(amiloride)-235.6(PD)-230.8(after)-232.1(40\26150)-231.3(min.)-230(The)-237.2(action)-232(of)-230.7(amiloride)-235.6(remains)-229.1(for)-235.9(up)-230.5(to)]TJ 0 -1.0599 TD [(4)-332.2(h)-332.2([14])-333.4(\(data)-331.5(not)-323.3(shown\).)]TJ ET 3.864 M /GS3 gs 343.793 336.971 m 343.793 205.972 l 343.793 206.198 m 531.292 206.198 l 343.668 206.234 m 341.856 206.234 l 343.793 223.296 m 341.981 223.296 l 343.793 239.046 m 341.981 239.046 l 343.793 254.796 m 341.981 254.796 l 343.668 271.359 m 341.856 271.359 l 343.713 287.553 m 341.9 287.553 l 343.685 304.582 m 341.872 304.582 l 343.872 320.457 m 342.06 320.457 l 343.918 336.729 m 342.106 336.729 l S BT /F17 1 Tf 10 0 0 10 328.156 333.097 Tm 0 0 0 1 k /GS4 gs -0.0016 Tc (-40)Tj 0.0427 -1.5796 TD (-35)Tj -0.037 -1.6332 TD (-30)Tj -0.0033 -3.3007 TD 0 Tc (-20)Tj 0.0432 -1.6833 TD -0.0016 Tc (-15)Tj -0.0455 -1.5738 TD 0 Tc (-10)Tj 0.4647 -1.554 TD (-5)Tj 0.2467 -1.7015 TD (0)Tj -0.6728 8.1263 TD -0.0079 Tc (-25)Tj ET /GS3 gs 343.793 206.198 m 343.793 204.097 l 374.73 206.215 m 374.73 204.114 l 406.177 206.203 m 406.177 204.102 l 437.482 206.333 m 437.482 204.232 l 469.127 206.265 m 469.127 204.163 l 500.263 206.281 m 500.263 204.18 l 531.087 206.326 m 531.087 204.225 l S BT 10 0 0 10 525.917 194.222 Tm /GS4 gs 0 Tc (30)Tj -3.0125 0 TD (25)Tj -3.1351 0 TD (20)Tj -3.1649 0 TD -0.0116 Tc (15)Tj -3.1535 0 TD 0 Tc (10)Tj -2.8764 0 TD (5)Tj -3.109 0 TD (0)Tj 7.7764 -1.7 TD [(T)18(ime min)]TJ 0 10 -10 0 318.543 257.972 Tm (PD mV)Tj ET 3.864 M /GS3 gs 354.793 329.972 m 354.793 334.096 l S 354.793 330.263 m 356.543 330.263 l 354.793 325.888 l 353.043 330.263 l 354.793 330.263 l f* BT 10 0 0 10 357.168 326.222 Tm /GS4 gs (Basal)Tj ET /GS3 gs 380.543 329.972 m 380.543 334.096 l S 380.543 330.263 m 382.293 330.263 l 380.543 325.888 l 378.793 330.263 l 380.543 330.263 l f* BT 10 0 0 10 382.418 326.096 Tm /GS4 gs (Amiloride)Tj ET /GS3 gs 418.951 329.972 m 418.951 334.096 l S 418.951 330.263 m 420.701 330.263 l 418.951 325.888 l 417.201 330.263 l 418.951 330.263 l f* BT 10 0 0 10 421.472 326.096 Tm /GS4 gs -0.0199 Tc (UTP)Tj ET /GS3 gs 447.418 329.972 m 447.418 334.096 l S 447.418 330.263 m 449.167 330.263 l 447.418 325.888 l 445.668 330.263 l 447.418 330.263 l f* BT 10 0 0 10 449.668 326.096 Tm /GS4 gs (UTP)Tj ET /GS3 gs 343.668 280.722 m 345.168 282.097 l 346.043 283.472 l 346.418 285.722 l 346.543 287.347 346.793 287.597 v 347.043 287.847 347.543 289.972 y 348.543 291.347 l 349.918 292.097 l 351.293 291.972 l 352.543 292.222 l 354.168 294.722 l 356.418 296.847 l 357.918 298.847 l 359.168 299.347 l 360.418 299.972 l 361.543 299.722 l 362.668 298.972 l 363.918 298.472 l 365.543 298.722 l 367.043 298.972 l 368.668 298.222 l 370.293 296.972 l 371.918 295.222 l 373.668 293.472 l 375.293 290.847 l 375.668 288.347 l 376.418 283.972 l 377.043 280.597 l 377.543 276.347 l 378.168 273.597 l 378.543 270.847 l 378.793 267.847 l 379.168 263.847 l 379.543 261.347 l 380.043 259.597 l 381.168 257.722 l 382.043 256.722 l 383.293 256.347 l 384.793 256.597 l 386.418 257.347 l 388.543 258.347 l 390.668 258.972 l 392.668 259.097 l 394.918 258.722 l 396.293 257.597 l 397.293 256.972 397.543 256.972 v 397.793 256.972 398.668 257.097 398.918 257.222 c 399.168 257.347 400.918 258.222 y 402.418 258.222 l 404.668 257.222 l 407.293 256.472 l 408.418 255.472 l 409.793 254.347 l 411.168 253.097 l 412.418 251.972 l 413.293 250.722 l 414.793 249.972 l 416.918 249.347 l 418.418 248.847 418.668 248.847 v 418.918 248.847 420.418 249.222 y 421.543 250.222 l 423.043 251.972 l 424.918 254.472 l 426.543 256.222 l 427.918 258.222 l 429.418 259.972 l 431.168 261.472 l 433.418 262.472 l 435.793 263.222 l 438.043 263.347 l 440.168 263.472 l 442.543 263.472 l 444.667 263.222 l 446.793 262.722 l 449.042 262.472 l 450.542 262.722 450.667 263.097 v 450.793 263.472 451.292 264.722 y 452.042 267.847 l 452.917 271.472 l 453.418 273.972 l 453.917 275.597 l 454.417 278.597 l 454.792 281.222 l 455.917 283.847 l 457.667 285.222 l 459.542 285.972 l 461.542 285.847 l 463.917 285.722 l 467.417 285.722 l 469.167 285.222 l 471.042 284.847 l 473.417 284.722 l 474.917 284.722 l 476.292 285.222 l 477.292 286.222 477.417 286.597 v 477.542 286.972 477.417 288.347 y 477.542 291.972 l 478.167 295.722 l 478.167 300.222 l 478.542 303.472 l 479.292 306.347 l 480.042 307.972 l 481.667 309.222 l 483.667 311.472 l 485.042 311.972 l 486.542 312.597 l 487.542 314.847 l 488.667 316.222 l 490.542 317.597 l 492.417 318.347 l 494.792 318.097 l 495.542 317.347 l 496.417 316.597 l 497.417 316.847 l 498.792 317.472 l 499.917 317.097 l 501.042 316.472 l 502.167 317.097 l 503.167 318.097 l 504.667 318.221 l 505.792 317.722 l 506.792 317.846 l 508.167 318.971 l 509.542 319.097 l 511.542 318.847 l S BT /F3 1 Tf 7.97 0 0 7.97 309.543 163.446 Tm 0 g /GS2 gs 0 Tc [(Fig.)-327.1(4.)-331.2(\261)-332.2(The)-322.6(nasal)-332.5(potential)-322.9(diff)12.8(erence)-324.9(\(PD\))-326.6(changes)-324.9(with)-333.2(logarith)10.5(mic)]TJ 0 -1.067 TD [(increment)9.6(al)-274.6(doses)-275.4(of)-266.3(uridine)-273.8(triphosphate)-265.8(\(UTP\))-270.2(from)-269.7(0.1\26110)-265.9(mmol)]TJ /F11 1 Tf 27.0086 0.249 TD (.)Tj /F3 1 Tf 0.2703 -0.249 TD (L)Tj 5.977 0 0 5.313 531.779 158.513 Tm (-1)Tj 7.97 0 0 7.97 309.543 146.494 Tm [(in)-439.2(a)]TJ /F4 1 Tf 2.0841 0 TD (cftr)Tj /F3 1 Tf 5.977 0 0 5.313 336.983 150.009 Tm -0.0001 Tc (tm1HGU)Tj 7.97 0 0 7.97 362.551 146.494 Tm 0 Tc 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[(and)-406.7(the)-403.4(combinati)-12.3(on)-399.9(of)-407.2(both)-403.8(drugs)-404.9(n)-6.5(ormalize)-11.1(d)-399.1(the)-403.4(low)]TJ 0 -1.0527 TD [(perip)-8.2(heral)-338.7(mucoc)-7.8(iliary)-338.1(clear)-9(ance)-334.3(in)-339.7(CF)-335.5([24].)]TJ 1.0015 -1.0471 TD [(Pu)16.3(ri)17.3(ne)-434.4(an)20.8(d)-444.6(p)0(y)15.5(r)0(i)17.3(m)0(i)21.4(d)0(i)13.2(n)0(e)-434.4(n)0(u)21.2(c)0(l)18.5(e)0(o)15.1(t)0(i)16.5(d)0(e)20.8(s)-445.8(su)20(ch)-434.4(as)-435.6(ad)20.8(en)15.1(os)20(in)13.2(e)]TJ -1.0015 -1.0527 TD [(tr)17.3(ip)18.9(ho)15.5(sp)20(ha)15.1(te)-237.6(\(A)118.1(T)12.2(P)0(\))-241.3(a)0(n)20.8(d)-251.2(UT)18.9(P)-250.4(m)0(a)17.7(y)-245.5(ac)14.7(t)-247.8(o)0(n)-234.8(e)0(x)15.1(t)0(r)17.3(a)0(c)14.7(e)0(l)18.4(l)0(u)18.8(l)0(a)18.4(r)-247.1(P2)16.3(Y)]TJ T* [(re)19.2(ce)14.7(pt)18.9(or)14(s)-343.4(l)0(i)16.5(n)0(k)15.5(e)0(d)-337.7(t)0(o)-339.7(G)0(-)15.7(p)0(r)19.6(o)0(t)18.9(e)0(i)18.5(n)0(s)-338.5(t)0(o)-339.7(p)0(r)14(o)0(d)21.2(u)0(c)15.1(e)-348.3(C)11.6(a)]TJ 7.472 0 0 6.641 237.203 148.365 Tm (2+)Tj 9.963 0 0 9.963 248.485 143.887 Tm [(mo)18.1(bi)18.9(li)16.5(za)14.7(-)]TJ -19.0918 -1.0471 TD [(ti)16.5(on)-200.7(an)20.8(d)-211.3(C)0(l)]TJ 7.472 0 0 6.641 100.857 137.877 Tm (-)Tj 9.963 0 0 9.963 105.335 133.455 Tm [(se)19.6(cr)13.5(et)18.4(io)18.9(n)-211.3([)0(2)19.6(5].)-214.1(The)-223.1(CF)-221.7(mouse)-224.8(nasal)-224.4(tissue)-222.7(was)]TJ -4.7232 -1.0528 TD [(pretre)-11(ated)-307.8(with)-313.3(nebuli)-9.7(zed)-310.4(suramin)-315.7(\(100)]TJ /F9 1 Tf 16.127 0 TD (m)Tj /F3 1 Tf 0.5691 0 TD (mol)Tj /F11 1 Tf 1.5478 0.2049 TD (.)Tj /F3 1 Tf 0.2731 -0.2049 TD (L)Tj 7.472 0 0 6.641 248.768 127.389 Tm (-1)Tj 9.963 0 0 9.963 254.948 122.967 Tm [(\))-304(whi)-8.6(ch)]TJ -19.7405 -1.0471 TD [(is)-471.7(a)-467.8(compe)-7.8(titive)-475.4(antago)-7.8(nist)-469.9(of)-469.7(P2)-467.4(pu)-7.2(rinorecept)-11.1(ors)-471.7([26,)]TJ 25.1977 66.1583 TD [(27].)-368.5(Subseque)-7.3(nt)-362.4(nebuli)-9.7(zed)-361.6(appli)-9(cation)-368.7(of)-361.6(UTP)-362.4(up)-365.7(to)-362.4(10)]TJ 0 -1.0584 TD [(mm)-7.8(ol)]TJ /F11 1 Tf 2.3217 0.1992 TD (.)Tj /F3 1 Tf 0.2675 -0.1992 TD (L)Tj 7.472 0 0 6.641 341.178 765.524 Tm (-1)Tj 9.963 0 0 9.963 352.403 761.102 Tm [(fail)-9.8(ed)-514.1(to)-516.1(produce)-519.9(any)-514.8(nasal)-520.3(PD)-516.8(change)-517.9(in-)]TJ -4.3248 -1.0584 TD [(dicat)-9.4(ing)-334.7(that)-338.3(UTP)-339.6(probably)-340.5(acts)-337.5(on)-337.3(these)-338.2(recept)-9.8(ors.)]TJ 1.0015 -1.0527 TD [(Th)17.1(e)-223.1(a)0(c)20.4(t)0(i)16.5(o)0(n)-212.1(o)0(f)-213.7(U)0(T)18.9(P)-221.9(wa)16.9(s)-218.2(b)0(r)13.9(i)0(e)18.4(f)0(,)-213.3(l)0(a)18.4(s)0(t)17.7(i)0(n)18.8(g)-222.7(fo)19.6(r)-218.6(3)0(0)15.5(\261)0(4)15.5(0)-217(mi)15.7(n)-222.7(a)0(f)19.2(t)0(e)18.4(r)]TJ -1.0015 -1.0584 TD 0.2231 Tc [(ad)223.1(o)238.6(s)223.1(e)9.4(o)223.1(f)15.1(1)223.1(0)11(m)223.1(m)238(o)223.1(l)]TJ /F11 1 Tf 7.1985 0.1992 TD 0 Tc (.)Tj /F3 1 Tf 0.2731 -0.1992 TD (L)Tj 7.472 0 0 6.641 389.707 733.946 Tm (-1)Tj 9.963 0 0 9.963 395.66 729.524 Tm [(.)-222.3(A)12.4(tt)16.5(em)17.7(pt)13.2(s)-218.2(w)0(e)16.9(r)0(e)-214.1(m)0(a)17.7(d)0(e)-212.5(t)0(o)-214.5(p)0(r)19.6(o)0(l)13.2(o)0(n)21.2(g)-222.7(th)18.9(e)]TJ -8.6667 -1.0584 TD [(ac)14.7(ti)16.5(on)-303.1(of)-299(UT)13.2(P)-307.3(b)0(y)-303.1(t)0(h)18.9(e)-314.2(ad)20.8(di)13.2(t)13.9(i)0(o)13.2(n)-308.1(of)-304.7(10)-303.1(mm)20.6(ol)]TJ /F11 1 Tf 16.9806 0.1992 TD (.)Tj /F3 1 Tf 0.2675 -0.1992 TD (L)Tj 7.472 0 0 6.641 487.105 723.401 Tm (-1)Tj 9.963 0 0 9.963 496.233 718.979 Tm [(al)18.4(ph)15.5(a)-314.2(b)0(e)20.8(t)0(a)]TJ -18.7617 -1.0584 TD [(me)12(th)18.8(yl)18.9(en)15.1(e-)19.2(ad)15.1(en)20.8(os)20(in)13.2(e)-251.6(5)]TJ /F10 1 Tf 8.9968 0 TD (')Tj /F3 1 Tf 0.4666 0 TD [(di)13.2(ph)21.2(os)14.4(ph)21.2(at)18.5(e)-251.6(\()0(A)15.7(M)0(P)14.4(-)0(C)20.6(P)0(\))14.7(,)-250.8(a)-251.6(b)0(l)18.9(o)0(c)15.1(k)0(e)20.8(r)]TJ -9.4634 -1.0584 TD [(of)-424.2(ec)20.4(to)18.9(nu)15.5(cl)18.5(eo)15.1(si)17.7(da)20.8(se)13.9(s,)-417.7(wh)17.3(ic)18.4(h)-427.6(r)0(e)13.5(g)0(u)21.2(l)0(a)12.8(t)0(e)18.4(s)-428.7(th)18.9(e)-428(b)0(r)13.9(e)0(a)20.4(k)0(d)15.5(o)0(w)17.3(n)-427.6(of)]TJ T* [(mo)12.4(no)21.2(ph)15.5(os)20(ph)15.5(at)18.4(es)-407.2(to)-407.9(pu)21.2(ri)17.3(ne)15.1(/p)18.8(yr)13.9(im)15.7(i)13.9(d)0(i)13.2(n)0(e)-406(+)-416.8(ph)21.2(os)14.4(ph)21.2(at)12.8(e)-416.6([)0(2)19.6(8].)]TJ T* [(How)-10.2(ever)28.7(,)-290.6(this)-293.5(was)-298(inef)9.6(fecti)-11(ve,)-292.5(sugges)-7.4(ting)-292.3(that)-292.7(the)-295.3(break-)]TJ 0 -1.0641 TD [(down)-405.3(of)-407.2(uridine)-404.7(monop)-7(hosphat)-9.3(e)-399.5(\(UM)-9.8(P\))-400.7(to)-402.3(uridi)-10.2(ne)-400.3(and)]TJ 0 -1.0584 TD [(pho)-8(sphate)-424.4(is)-420.5(not)-420.1(the)-426.2(rate)-423.2(limit)-10.8(ing)-420.1(step)-422.4(in)-425(the)-420.5(action)-425.6(of)]TJ T* [(UTP)98.6(.)]TJ 1.0015 -1.0471 TD [(Ph)16.3(en)15.1(ot)18.9(yp)15.5(i)13.9(c)-513.3(an)15.1(d)-512.9(e)0(l)18.5(e)0(c)20.4(t)0(r)17.3(o)0(p)15.5(h)0(y)21.2(s)0(i)17.7(o)0(l)13.2(o)0(g)21.2(i)0(c)18.4(a)0(l)-505.1(d)0(i)18.9(f)14.7(fe)19.2(re)19.2(nc)15.1(es)-503.9(ex)20.8(is)17.7(t)]TJ -1.0015 -1.0584 TD [(be)15.1(tw)14.9(ee)20.4(n)-347.9(C)11.6(F)-347.1(a)0(f)24.9(f)0(e)19.2(c)0(t)18.5(e)0(d)-337.7(h)0(u)15.5(m)0(a)17.7(n)-342.2(su)14.4(bj)18.9(ec)14.7(ts)-335.2(an)20.8(d)-347.9(m)0(o)18.1(u)0(s)14.3(e)-342.6(mo)18.1(de)15.1(ls)17.7(.)]TJ 0 -1.0641 TD [(Th)17.1(is)-483.1(pa)20.8(rt)17.3(ly)-481.9(re)13.5(fl)17.3(ec)20.4(ts)-483.1(th)18.9(e)-490.6(p)0(r)19.6(o)0(p)15.5(o)0(r)19.6(t)0(i)16.5(o)0(n)15.5(a)0(l)-476.6(s)0(p)14.4(e)0(c)20.4(i)0(e)18.5(s)-491.3(di)18.9(f)14.7(f)0(e)19.2(r)0(e)19.2(n)0(c)15.1(e)0(s)]TJ 0 -1.0584 TD [(be)15.1(tw)14.9(ee)20.4(n)-478.8(t)0(h)18.8(e)-473.5(tw)14.9(o)-473.1(m)0(a)12(i)13.9(n)-478.8(C)11.6(l)]TJ 7.472 0 0 6.641 415.729 607.408 Tm (-)Tj 9.963 0 0 9.963 422.872 602.986 Tm [(ch)15.1(an)20.8(ne)15.1(ls)-466(in)-464.8(th)13.2(e)-473.5(a)0(i)18.4(r)0(w)15.7(a)0(y)-468.6(e)0(p)20.8(i)0(-)]TJ -11.3982 -1.0584 TD [(th)13.2(el)18.4(iu)18.8(m,)-209.1(\(t)17.3(he)-201.1(CF)17.3(TR)-209.5(Cl)]TJ 7.472 0 0 6.641 396.34 596.863 Tm (-)Tj 9.963 0 0 9.963 400.932 592.441 Tm [(ch)20.8(an)15.1(ne)20.8(ls)-210(an)20.8(d)-217(t)0(h)18.9(e)-211.7(Ca)]TJ 7.472 0 0 6.641 478.034 596.863 Tm 0.0001 Tc (2+)Tj 9.963 0 0 9.963 488.012 592.441 Tm 0 Tc [(ac)14.7(ti)16.5(va)20.8(te)18.4(d)-217(C)0(l)]TJ 7.472 0 0 6.641 534.047 596.863 Tm (-)Tj 9.963 0 0 9.963 309.316 581.896 Tm [(ch)15.1(an)15.1(ne)20.8(ls)17.7(\))-264.1([)0(2)19.6(9],)-265.3(and)-275.8(also)-274.5(the)-278.2(expres)-8.2(sion)-274.1(of)-270.6(a)-274.3(propor)-7.8(tion)-275.3(of)]TJ T* [(wi)-7.8(ld)-476.2(type)-478.2(CFTR)-482.4([30])-478.6(in)-476.2(the)-483.1(mutant)-479.5(mous)-7.4(e)-473.5(lung.)-483.8(The)]TJ T* [(incl)-8.2(usion)-519.5(of)-509.6(functional)-529.3(CFTR,)-522.7(introduced)-526.9(to)-516.1(mai)-8.2(ntain)]TJ T* [(viabi)-9(lity)58.1(,)-455.6(may)-461.1(explain)-460.5(why)-461.5(the)-454.6(Edinburgh)-453.1(CF)-460.7(mice)-458.9(in)]TJ 0 -1.0641 TD [(parti)-10.6(cular)-293.1(have)-294.1(low)-8.6(er)-293.7(than)-290.4(expec)-10.7(ted)-289.6(nasal)-298.4(epitheli)-10.7(al)-288.8(PDs.)]TJ 0 -1.0584 TD [(In)-344.6(the)-340.8(muri)-10.2(ne)-337.7(bo)-7.2(wel)-339.1(h)-6.5(owever)23.2(,)-336.1(CFTR)-345.9(medi)-9(ated)-342(Cl)]TJ 7.472 0 0 6.641 512.164 533.537 Tm (-)Tj 9.963 0 0 9.963 518.003 529.115 Tm (tran-)Tj -20.9469 -1.0584 TD [(sport)-242.3(plays)-241.1(a)-240.2(major)-239(role)-240.7(and)-241.7(alternative)-248.7(Ca)]TJ 7.472 0 0 6.641 475.88 522.992 Tm (2+)Tj 9.963 0 0 9.963 486.198 518.57 Tm [(mediated)-242.8(Cl)]TJ 7.472 0 0 6.641 534.047 522.992 Tm (-)Tj 9.963 0 0 9.963 309.316 508.025 Tm [(secret)-11(ion)-249.4(is)-244.1(absent)-248([27].)-251.3(Fatal)-253.3(bowel)-249.5(obstructi)-11.5(on)-246.2(therefore)]TJ T* [(occ)-8.8(urs)-227(in)-225.8(a)-223.1(large)-224.8(proportion)-231.8(of)-230.7(knockout)-230.8(CF)-227.4(mic)-8.2(e)-223.1(because)]TJ T* [(they)-512.3(have)-504.6(no)-508(residual)-509.5(CFTR)-10.1(.)-501.2(However)18.5(,)-501.2(inte)-8.2(stinal)-508.4(ob-)]TJ T* [(stru)-8.2(ction)-236.6(and)-236(poor)-226.6(grow)-8.6(th)-231.5(was)-241.1(rare)-234.7(in)-237.2(the)-232.7(Edi)-8.8(nburgh)-228.1(mice)]TJ T* [(bec)-8.8(ause)-414.8(they)-415.6(expres)-8.2(s)-411.7(a)-410.9(propor)-7.8(tion)-417.5(of)-412.8(wild)-421.5(type)-415.6(CFTR.)]TJ 0 -1.0641 TD [(Thu)-6.4(s)-275.1(the)-272.5(propor)-7.8(tion)-275.3(of)-264.9(funct)-8.2(ional)-276.4(CFTR)-277.6(expres)-8.2(sed)-277(in)-271.4(the)]TJ 0 -1.0584 TD [(Edi)-8.8(nburgh)-256.6(mous)-7.4(e)-262.9(may)-267.6(limit)-266.9(the)-266.8(useful)-10.1(ness)-267.6(of)-264.9(this)-270.8(model.)]TJ 1.0015 -1.0471 TD [(In)-247.8(co)15.1(nt)18.9(ra)19.2(st)-244.1(to)-248.6(th)18.9(e)-257.2(E)12.2(di)18.9(nb)15.5(ur)31(gh)-246.2(mo)18.1(de)15.1(l)-253.5(t)0(h)18.8(e)]TJ /F8 1 Tf 15.3531 0 TD (D)Tj /F3 1 Tf 0.6544 0 TD [(F5)16.3(08)-246.2(mo)18.1(de)15.1(l)-253.5(o)0(f)]TJ -17.0091 -1.0584 TD [(CF)-369.7(mo)18.1(us)20(e)-376.7(h)0(a)20.8(s)-377.5(in)18.8(cr)19.2(ea)14.7(se)19.6(d)-376.3(b)0(a)20.8(s)0(a)13.9(l)-373(P)11.4(D)-374.6(ch)15.1(an)20.8(ge)15.1(s)-371.8(a)0(n)15.1(d)-370.7(sh)14.4(ow)17.3(s)-371.8(a)]TJ T* [(la)12.8(r)20.4(g)0(e)20.8(r)-207.2(re)19.2(sp)14.4(on)21.2(se)-196.6(to)-191.7(so)14.3(di)18.9(um)-192.5(ch)15.1(an)20.8(ne)15.1(l)-202.3(b)0(l)18.9(o)0(c)15.1(k)0(e)20.8(r)0(s)-197.8(a)0(n)15.1(d)-199.9(UT)18.9(P)108.1(.)-199.6(Si)19.6(nc)15.1(e)]TJ 0 -1.0641 TD [(th)13.2(is)-431.9(mo)18.1(de)20.8(l)-441.3(c)0(a)14.7(r)0(r)18(i)0(e)18.4(s)-440.1(th)13.2(e)-439.3(m)0(u)18.1(t)0(a)18.4(t)0(i)16.5(o)0(n)-434(a)0(f)30.6(f)0(e)13.5(c)0(t)18.5(i)0(n)18.9(g)-438.9(up)-434(to)-430.7(80)15.5(%)-441.3(o)0(f)]TJ 0 -1.0584 TD [(hu)15.5(ma)17.7(n)-291(C)11.6(F)-290.2(p)0(a)15.1(t)13.9(ie)12.8(nt)18.9(s)-286.5(i)0(t)-279.4(m)0(a)12(y)-285.3(be)-280.8(mo)18.1(re)-282.4(re)19.2(le)18.4(va)15.1(nt)-277.1(mo)18.1(de)15.1(l)-287.7(f)0(o)13.9(r)-286.9(th)18.9(e)]TJ T* [(st)17.7(ud)15.5(y)-325.1(o)0(f)-316.1(h)0(u)21.2(m)0(a)17.7(n)-325.1(di)18.9(se)14(as)19.6(e.)]TJ 1.0015 -1.0471 TD [(Lo)17.1(ng)-394.2(ac)20.4(ti)16.5(ng)-394.2(so)20(di)18.9(um)-397.3(ch)20.8(an)15.1(ne)20.8(l)-401.5(b)0(l)18.9(o)0(c)15.1(k)0(e)15.1(r)0(s)-391.3(s)0(u)20(c)0(h)-394.6(a)0(s)-390.1(l)0(o)18.8(p)0(e)15.1(r)0(a)19.2(-)]TJ -1.0015 -1.0641 TD 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Tf 5.4946 0 TD (1987;)Tj -20.5495 -1.1255 TD [(80:)-336(1523\2611526.)]TJ -2.5165 -1.1128 TD [(2.)-1766.5(Puchelle)-378(E,)-378.9(Gaillard)-386.3(D,)-378.7(Ploton)-379.7(D,)]TJ /F4 1 Tf 16.8063 0 TD [(et)-380.5(al)]TJ /F3 1 Tf 1.8589 0 TD [(.)-376(Different)6.7(ial)-382.4(lo-)]TJ -16.1487 -1.1192 TD [(calization)-642.1(of)-644.9(the)-639.3(cystic)-647.4(fibrosis)-643.6(transmembrane)-646.6(con-)]TJ T* [(ductance)-402.1(regulator)-400(in)-393.4(normal)-400.3(and)-402.9(cystic)-394.5(fibrosis)-403.3(airway)]TJ 0 -1.1255 TD (epithelium.)Tj /F4 1 Tf 4.7359 0 TD [(Am)-258.7(J)-258.5(Respir)-257.9(Cell)-260.1(Mol)-260.5(Biol)]TJ /F3 1 Tf 10.7742 0 TD [(1992;)-259.1(7:)-260.6(485\261491.)]TJ -18.0266 -1.1065 TD [(3.)-1766.5(Rugolo)-345.5(M,)-350.8(Mastrocola)-349.6(T)72.9(,)-350.7(Whorle)-347.1(C,)]TJ /F4 1 Tf 17.7864 0 TD [(et)-348.9(al)]TJ /F3 1 Tf 1.8273 0 TD [(.)-350.7(A)104.7(TP)-348.8(and)-346(A1)]TJ -17.0971 -1.1255 TD [(adenosine)-207(receptor)-214.5(agonists)-211.5(mobilize)-213.2(intracellular)-215(calcium)]TJ 0 -1.1192 TD [(and)-453.5(activate)-457.4(K)]TJ 6.725 0 0 5.977 386.759 116.504 Tm (+)Tj 8.966 0 0 8.966 394.639 112.535 Tm [(and)-453.5(Cl)]TJ 6.725 0 0 5.977 419.981 116.504 Tm (-)Tj 8.966 0 0 8.966 426.217 112.535 Tm [(currents)-456.2(in)-450.3(normal)-457.2(and)-453.5(cystic)]TJ 10.7995 76.3934 TD (149)Tj 7.472 0 0 7.472 204.038 797.499 Tm 0.0001 Tc [(SODIUM)-335.6(CHANN)-12.6(EL)-332.1(BLOCKERS)-344.4(AND)-334.5(UTP)-333.8(IN)-340.8(CF)-329.7(MICE)]TJ ET endstream endobj 29 0 obj << /ProcSet [/PDF /Text ] /Font << /F3 6 0 R /F4 7 0 R /F6 9 0 R /F8 11 0 R /F9 12 0 R /F10 13 0 R /F11 19 0 R >> /ExtGState << /GS2 14 0 R >> >> endobj 31 0 obj << /Length 15247 >> stream BT /F3 1 Tf 8.966 0 0 8.966 80.844 772.157 Tm 0 g /GS2 gs 0 Tc [(fibrosis)-378.1(airway)-376.2(epithelial)-385.5(cells.)]TJ /F4 1 Tf 12.8671 0 TD [(J)-372.3(Biol)-379.3(Chem)]TJ /F3 1 Tf 5.5325 0 TD [(1993;)-379.2(268:)]TJ -18.3997 -1.1381 TD (24779\26124784.)Tj -2.5165 -1.1128 TD [(4.)-1766.5(Kunzelmann)-577.1(K,)-574.8(Kathofer)-584.8(S,)-576.4(Greger)-577.1(R.)-582.5(Na)]TJ 6.725 0 0 5.977 247.805 755.943 Tm 0 Tw (+)Tj 8.966 0 0 8.966 256.762 751.975 Tm [(and)-580(Cl)]TJ 6.725 0 0 5.977 283.238 755.943 Tm (-)Tj 8.966 0 0 8.966 80.844 741.77 Tm [(conductances)-502.1(in)-500.9(airway)-509(epithehal)-507.7(cells:)-504.3(increased)-504.9(Na)]TJ 6.725 0 0 5.977 281.65 745.738 Tm (+)Tj 8.966 0 0 8.966 80.844 731.565 Tm [(conductance)-324.4(in)-330.2(cystic)-331.2(fibrosis.)]TJ /F4 1 Tf 12.5447 0 TD [(Pflugers)-328.8(Ar)27.9(ch)]TJ /F3 1 Tf 5.9056 0 TD [(1995;)-328.6(431:)]TJ -18.4503 -1.1381 TD (1\2619.)Tj -2.5165 -1.1128 TD [(5.)-1766.5(Rayner)-444.8(CF)67.3(,)-445.5(Rutman)-448.3(A,)-448.3(Dewar)-453.5(A,)-448.3(Cole)-447.4(PJ,)-450.6(W)32.8(ilson)-452.3(R.)]TJ 2.5165 -1.1381 TD [(Ciliary)-337.8(disorientation)-335.3(in)-336.5(patients)-338.9(with)-341.1(chronic)-334.4(upper)-333.3(res-)]TJ T* [(piratory)-343.8(tract)-344.2(inflammation.)]TJ /F4 1 Tf 11.4571 0 TD [(Am)-340.9(J)-340.7(Respir)-346.4(Crit)-343.8(Car)33.6(e)-340.7(Med)]TJ /F3 1 Tf -11.4571 -1.1381 TD [(1995;)-328.6(151:)-335.5(800\261804.)]TJ -2.5165 -1.1128 TD [(6.)-1766.5(Knowles)-423.7(MR,)-430.9(Church)-426(NL,)-426(W)70.8(altner)-425.9(WE,)]TJ /F4 1 Tf 19.797 0 TD [(et)-424.8(al)]TJ /F3 1 Tf 1.9032 0 TD [(.)-426.6(A)-426.4(pilot)]TJ -19.1837 -1.1381 TD [(study)-361.4(of)-360.4(aerosolized)-367.1(amiloride)-365.4(for)-367.1(the)-361(treatment)-365.1(of)-366.7(lung)]TJ T* [(disease)-240.8(in)-248(cystic)-242.7(fibrosis.)]TJ /F4 1 Tf 10.104 0 TD [(N)-244.5(Engl)-244.1(J)-245.9(Med)]TJ /F3 1 Tf 5.7159 0 TD [(1990;)-246.4(322:)-240.6(1)32.1(189\261)]TJ -15.8199 -1.1444 TD [(1)32.1(194.)]TJ -2.5165 -1.1065 TD [(7.)-1766.5(Smith)-407.3(JJ,)-415.3(T)34.9(ravis)-412.8(SM,)-412.1(Greenberg)-404.6(EP)106.4(,)-407.6(W)70.8(elsh)-412.3(MJ.)-408.4(Cystic)]TJ 2.5165 -1.1381 TD [(fibrosis)-416(airway)-420.4(epithelia)-415.3(fail)-420.8(to)-418.7(kill)-416.1(bacteria)-418.1(because)-420.4(of)]TJ 0 -1.1444 TD [(abnormal)-335.8(airway)-331.9(surface)-334(fluid.)]TJ /F4 1 Tf 12.7154 0 TD (Cell)Tj /F3 1 Tf 1.9727 0 TD [(1996;)-334.9(85:)-336(229\261236.)]TJ -17.2046 -1.1065 TD [(8.)-1766.5(Knowles)-651.3(MR,)-652.2(Robinson)-649.1(JM,)-655(W)77.1(ood)-656.1(RE,)]TJ /F4 1 Tf 20.9794 0 TD [(et)-652.4(al)]TJ /F3 1 Tf 2.1308 0 TD [(.)-647.8(Ion)]TJ -20.5937 -1.1381 TD [(composition)-516.5(of)-512.1(airway)-515.3(surface)-517.4(liquid)-516.3(of)-512.1(patients)-516(with)]TJ 0 -1.1444 TD [(cystic)-520.9(fibrosis)-529.8(as)-518.4(compared)-529.2(with)-524.5(normal)-520.4(and)-523.1(disease-)]TJ 0 -1.1381 TD [(control)-330.7(subjects.)]TJ /F4 1 Tf 6.8983 0 TD [(J)-334.4(Clin)-336.2(Invest)]TJ /F3 1 Tf 5.5009 0 TD [(1997;)-334.9(100:)-329.1(2588\2612595.)]TJ -14.9157 -1.1065 TD [(9.)-1766.5(Mason)-561.8(S,)-557.4(Paradiso)-561.3(AM,)-562.3(Boucher)-564.4(RC.)-561.4(Regulation)-569(of)]TJ 2.5165 -1.1381 TD [(transepithehal)-364(ion)-367.6(transport)-369.8(and)-365(intracellular)-373(calcium)-369.1(by)]TJ 0 -1.1445 TD [(extracellular)-225(adenosine)-219.6(triphosphate)-224(in)-222.7(human)-220.4(normal)-223.2(and)]TJ 0 -1.1381 TD [(cystic)-324.9(fibrosis)-327.5(airway)-331.9(epithelium.)]TJ /F4 1 Tf 13.727 0 TD [(Br)-326.1(J)-328.1(Pharmacol)]TJ /F3 1 Tf 6.8224 0 TD (1991;)Tj -20.5495 -1.1381 TD [(103:)-329.1(1649\2611656.)]TJ -2.5165 -1.1128 TD [(10.)-1266.5(Galietta)-349.5(LJ,)-348(Zegarra-Moran)-348.2(O,)-347.1(Mastrocola)-355.9(T)72.9(,)-344.4(W)70.8(ohrle)-348.3(C,)]TJ 2.5165 -1.1381 TD [(Rugolo)-257(M,)-256(Romeo)-263.1(G.)-258.6(Activation)-260.2(of)-265.5(Ca\()]TJ 6.725 0 0 5.977 223.313 502.186 Tm 0.0001 Tc (2+)Tj 8.966 0 0 8.966 230.457 498.16 Tm 0 Tc [(\)-dependent)-263.6(K)]TJ 6.725 0 0 5.977 281.65 502.186 Tm (+)Tj 8.966 0 0 8.966 80.844 487.956 Tm 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[(model)-267(for)-272.3(cystic)-268(fibrosis)-270.6(made)-271.3(by)-270.9(gene)-269.4(tar)11(geting.)]TJ /F4 1 Tf 19.797 0 TD (Science)Tj /F3 1 Tf -19.797 -1.1381 TD [(1992;)-328.6(257:)-335.5(1083\2611088.)]TJ -2.5165 -1.1128 TD [(15.)-1266.5(Davidson)-204.9(DJ,)-208.7(Dorin)-212.8(JR,)-210.1(McLachlan)-209.7(G,)]TJ /F4 1 Tf 18.0203 0 TD [(et)-209.8(al)]TJ /F3 1 Tf 1.6882 0 TD [(.)-211.6(Lung)-203.8(disease)]TJ -17.192 -1.1381 TD [(in)-380.8(the)-380(cystic)-381.8(fibrosis)-384.4(mouse)-379.7(exposed)-382.9(to)-380.8(bacterial)-382(patho-)]TJ T* (gens.)Tj /F4 1 Tf 2.4027 0 TD [(Natur)32.2(e)-334.4(Genetics)]TJ /F3 1 Tf 6.854 0 TD [(1995;)-328.6(9:)-336.5(351\261357.)]TJ -11.7733 -1.1128 TD [(16.)-1266.5(Ghosal)-250.2(S,)-253.9(T)60.2(aylor)-253.5(CJ,)-254.4(McGaw)-250.9(J.)-256.5(Modification)-251.2(of)-259.2(the)-253.6(nasal)]TJ 2.5165 -1.1381 TD [(membrane)-221.3(potential)-219.5(difference)-214.3(with)-221(inhaled)-222.1(amiloride)-219.9(and)]TJ T* [(loperamide)-425.5(in)-431.3(the)-424.3(CF)-432.2(mouse.)]TJ /F4 1 Tf 12.6205 0 TD (Thorax)Tj /F3 1 Tf 3.3006 0 TD [(1996;)-429.8(51:)-424.5(1229\261)]TJ -15.9211 -1.1381 TD (1232.)Tj -2.5165 -1.1128 TD [(17.)-1266.5(Unal-Maelger)-294.5(OH,)-286.7(Urbanek)-297.4(R.)-291.6(Status)-292.1(of)-290.8(determining)-294.8(the)]TJ 2.5165 -1.1381 TD [(transepithehal)-275.5(potential)-270.1(difference)-264.8(\(PD\))-273.7(of)-271.8(the)-272.5(respiratory)]TJ 27.9978 56.5584 TD [(epithelium)-593.9(in)-589.4(the)-588.7(diagnosis)-590.4(of)-588(mucoviscidosis.)]TJ /F4 1 Tf 20.6759 0 TD (Mon-)Tj -20.6759 -1.1128 TD [(atsschrift)-336.6(Kinderheilhm)9.2(de)]TJ /F3 1 Tf 10.7237 0 TD [(1988;)-334.9(136:)-335.5(76\26180.)]TJ -13.2402 -1.1128 TD [(18.)-1266.5(Hardcastle)-333(J,)-332.4(Hardcastle)-333(PT)74.8(,)-331.7(Read)-331(NW)80.6(,)-325.4(Redfern)-331.4(JS.)-330.5(The)]TJ 2.5165 -1.1065 TD [(action)-330.1(of)-328.8(loperamide)-336.9(in)-330.2(inhibiting)-329.3(prostaglandin-induced)]TJ 0 -1.1128 TD [(intestinal)-336.3(secretion)-336.8(in)-336.5(the)-335.8(rat.)]TJ /F4 1 Tf 12.1021 0 TD [(Br)-332.5(J)-334.4(Pharmacol)]TJ /F3 1 Tf 6.8414 0 TD [(1981;)-334.9(74:)]TJ -18.9434 -1.1128 TD (563\261569.)Tj -2.5165 -1.1065 TD [(19.)-1266.5(ABPI)-416.5(compendium)-417.9(of)-417.3(data)-417.2(sheets.)-415.1(London,)-414.3(Datapharm)]TJ 2.5165 -1.1128 TD [(Limited,)-334.1(1996\26197;)-333.4(pp.)-337(452\261648.)]TJ -2.5165 -1.1128 TD [(20.)-1266.5(Grubb)-229.3(B,)-228.4(V)47.8(ick)-228.3(RN,)-231.2(Boucher)-235.6(RC.)-226.3(Hyperabsorption)-237(of)-227.6(Na)]TJ 6.725 0 0 5.977 532.686 696.416 Tm (+)Tj 8.966 0 0 8.966 331.88 682.469 Tm [(and)-225.9(raised)-235(Ca\()]TJ 6.725 0 0 5.977 382.734 686.494 Tm 0.0001 Tc (2+)Tj 8.966 0 0 8.966 389.877 682.469 Tm 0 Tc [(\)-mediated)-236.7(Cl)]TJ 6.725 0 0 5.977 438.633 686.494 Tm (-)Tj 8.966 0 0 8.966 442.885 682.469 Tm [(secretion)-229.3(in)-229(nasal)-228.2(epithelia)]TJ -12.3803 -1.1065 TD [(of)-335.1(CF)-331.1(mice.)]TJ /F4 1 Tf 5.2038 0 TD [(Am)-334.6(J)-334.4(Physiol)]TJ /F3 1 Tf 5.7286 0 TD [(1994;)-334.9(266:)-335.5(C1478\261C1483.)]TJ -13.4488 -1.1128 TD [(21.)-1266.5(W)32.8(ilschanski)-339.1(MA,)-328.3(Rozmahel)-333(R,)-335.9(Beharry)-331.4(S,)]TJ /F4 1 Tf 20.1448 0 TD [(et)-336.3(al)]TJ /F3 1 Tf 1.8084 0 TD (.)Tj /F4 1 Tf 0.5817 0 TD [(In)-335.1(vivo)]TJ /F3 1 Tf -20.0183 -1.1128 TD [(measurements)-419.8(of)-417.3(ion)-418.2(transport)-414.1(in)-418.7(long)-417.7(living)-415.1(CF)-413.3(mice.)]TJ /F4 1 Tf T* [(Biochem)-334(Biophys)-332.1(Res)-338(Comm)]TJ /F3 1 Tf 12.0262 0 TD [(1996;)-334.9(219:)-335.5(753\261759.)]TJ -14.5427 -1.1065 TD [(22.)-1266.5(Knowles)-467.9(MR,)-468.9(Clarke)-472.4(LL,)-464.1(Boucher)-469.5(RC.)-466.6(Activation)-475.2(by)]TJ 2.5165 -1.1128 TD [(extracellular)-636(nucleotides)-640.7(of)-632.2(chloride)-633.5(secretion)-634(in)-633.7(the)]TJ T* [(airway)-243.4(epithelia)-244.5(of)-240.2(patients)-244.1(with)-246.3(cystic)-242.7(fibrosis.)]TJ /F4 1 Tf 18.9308 0 TD [(New)-248(Engl)]TJ 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Tf 3.7811 0 TD (')Tj /F3 1 Tf 0.215 0 TD [(-triphosphate)-483.7(+/-)-477.3(amiloride)-485.5(in)-475.6(normal)-482.5(human)]TJ -3.9961 -1.1065 TD (adults.)Tj /F4 1 Tf 2.9212 0 TD [(Am)-309.3(J)-302.8(Respir)-308.5(Crit)-312.1(Car)33.6(e)-309.1(Med)]TJ /F3 1 Tf 11.4951 0 TD [(1996;)-309.7(154:)-303.8(217\261223.)]TJ -16.9328 -1.1128 TD [(25.)-1266.5(Brown)-411.1(HA,)-406.8(Lazarowski)-410.2(ER,)-408.4(Boucher)-412.6(RC,)-409.7(Harden)-405.4(TK.)]TJ 2.5165 -1.1128 TD [(Evidence)-437.4(that)-432.5(UTP)-440.1(and)-434.5(A)104.7(T)0(P)-431(regulate)-443.6(phospholipase)-436.3(C)]TJ T* [(through)-297(a)-290.1(common)-297.6(extracellular)-294.5(5)]TJ /F10 1 Tf 13.6006 0 TD (')Tj /F3 1 Tf 0.5121 0 TD [(nucleotide)-292.2(receptor)-296.7(in)]TJ -14.1127 -1.1065 TD [(human)-308.9(airway)-313(epithelial)-309.6(cells.)]TJ /F4 1 Tf 12.3423 0 TD [(Mol)-311.1(Pharmacol)]TJ /F3 1 Tf 6.6264 0 TD [(1991;)-309.7(40:)]TJ -18.9687 -1.1128 TD (648\261655.)Tj -2.5165 -1.1128 TD [(26.)-1266.5(W)32.8(ilkinson)-212.9(GF)68.7(,)-211.6(Purkiss)-209.4(JR,)-210.1(Boarder)-217.6(MR.)-209.6(The)-210.4(regulation)-217.5(of)]TJ 2.5165 -1.1065 TD [(aortic)-716.7(endothelial)-724(cells)-717.5(by)-719.8(purines)-715.2(and)-719.1(pyrimidines)]TJ 0 -1.1128 TD [(involves)-545.4(co-existing)-547(P2y-purinoceptors)-548.4(and)-548.3(nucleotide)]TJ T* [(receptors)-512.4(linked)-507.3(to)-507.2(phosphohpase)-507.9(C.)]TJ /F4 1 Tf 15.959 0 TD [(Br)-509.5(J)-511.4(Pharmacol)]TJ /F3 1 Tf -15.959 -1.1128 TD [(1993;)-334.9(108:)-329.1(689\261693.)]TJ -2.5165 -1.1065 TD [(27.)-1266.5(Conigrave)-192.7(AD,)-185.5(Jiang)-190.5(L.)-189.2(Review:)-192.1(Ca\()]TJ 6.725 0 0 5.977 461.367 417.486 Tm 0.0001 Tc (2+)Tj 8.966 0 0 8.966 468.51 413.518 Tm 0 Tc [(\)-mobilizing)-190.4(recep-)]TJ -15.2382 -1.1128 TD [(tors)-306(for)-310.2(A)104.7(T)0(P)-310.9(and)-301.8(UTP)103.6(.)]TJ /F4 1 Tf 9.3832 0 TD [(Cell)-310.7(Calcium)]TJ /F3 1 Tf 5.6274 0 TD [(1995;)-303.3(17:)-310.7(1)32.1(1)32.1(1\2611)33.1(19.)]TJ -17.5271 -1.1128 TD [(28.)-1266.5(Richards)-542.2(SM,)-538.6(Dora)-545.8(KA,)-539.6(Rattigan)-544.8(S,)-538.4(Colquhoun)-540(EQ,)]TJ 2.5165 -1.1128 TD [(Clark)-416.3(MG.)-416.9(Role)-422.2(of)-417.3(extracellular)-421(UTP)-421.2(in)-412.4(the)-418(release)-423.7(of)]TJ 0 -1.1065 TD [(uracil)-242.5(from)-242.1(vasoconstricted)-242.2(hindlimb.)]TJ /F4 1 Tf 15.0991 0 TD [(Am)-246.1(J)-239.6(Physiol)]TJ /F3 1 Tf 5.4503 0 TD (1993;)Tj -20.5495 -1.1128 TD [(264:)-335.5(H233\261H237.)]TJ -2.5165 -1.1128 TD [(29.)-1266.5(Clarke)-681.1(LL,)-679.1(Grubb)-678.3(BR,)-681.5(Y)92(ankaskas)-674.2(JR,)-684.3(Cotton)-676.7(CU,)]TJ 2.5165 -1.1065 TD [(McKenzie)-342.8(A,)-340.8(Boucher)-343.1(RC.)-340.1(Relationship)-350.3(of)-341.4(a)-340.7(non-cystic)]TJ 0 -1.1128 TD [(fibrosis)-409.7(transmembrane)-412.7(conductance)-406.6(regulator)-412.6(mediated)]TJ T* [(chloride)-285.7(conductance)-280.2(to)-285.9(or)12.7(gan-level)-285(disease)-285.1(in)-279.6(CFTR\(-/-\))]TJ T* (mice.)Tj /F4 1 Tf 2.4976 0 TD [(Pr)27.9(oc)-333.9(Nafl)-329.9(Acad)-336.3(Sci)-335.8(USA)]TJ /F3 1 Tf 10.3443 0 TD [(1994;)-328.6(91:)-336(479\261483.)]TJ -15.3584 -1.1065 TD [(30.)-1266.5(Dorin)-339.2(JR,)-330.3(Stevenson)-338.6(BJ,)-336.6(Fleming)-336.5(S,)-336.1(Dickinson)-333.2(P)103.1(,)-338(Alton)]TJ 2.5165 -1.1128 TD [(EW)80.4(,)-464.5(Porteous)-473(DJ.)-474.3(Long)-469.4(term)-470.9(survival)-470.5(of)-474.2(the)-468.5(exon)-472(10)]TJ T* [(insertional)-271.2(cystic)-274.3(fibrosis)-270.6(mutant)-275.2(mouse)-272.2(is)-268.1(a)-271.2(consequence)]TJ T* [(of)-392(low)-396.2(level)-393.8(residual)-400.7(wild)-391.7(type)-398.5(CFTR)-388.8(gene)-395.9(expression.)]TJ /F4 1 Tf 0 -1.1065 TD [(Mamm)-333.8(Genome)]TJ /F3 1 Tf 6.7402 0 TD [(1994;)-328.6(5:)-336.5(465\261472.)]TJ -37.2546 59.4923 TD (150)Tj 7.472 0 0 7.472 265.436 797.499 Tm 0.0001 Tc 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