(Hypertension. 1997;30:596.)
© 1997 American Heart Association, Inc.
Articles |
Possible Involvement of Endothelium-Derived Hyperpolarizing Factor in Vascular Responses of Abdominal Aorta From Pregnant Rats
From the Departamento de Fisiología y Farmacología (R.A.B., E.C.H.), Sección de Graduados (C.C.H.), Escuela Superior de Medicina del IPN, Plan de San Luis y Díaz Mirón, Casco de Santo Tomás; and the Departamento de Farmacología (B.E.) and the Sección de Terapéutica Experimental (E.H.), CINVESTAV IPN, Mexico.
Correspondence to Rosa A. Bobadilla, MD, Dept de Fisiología y Farmacología, Escuela Superior de Medicina del IPN, Plan de San Luis y Díaz Mirón, Casco de Santo Tomás, Mexico DF, CP 11340.
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Abstract |
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Abstract Increased relaxant response to acetylcholine during pregnancy is proposed to be due to an estrogen-mediated increase in nitric oxide release. We studied acetylcholine-induced pathways of relaxation in the thoracic and abdominal aortic rings from pregnant and nonpregnant Wistar-Kyoto rats and measured basal and stimulated release of nitrites in these vessels. Endothelium-dependent relaxation was significantly greater in pregnant than in nonpregnant rats. Acetylcholine provoked a concentration-dependent relaxation on thoracic and abdominal aortic rings from nonpregnant and pregnant rats. After N118-nitro-L-arginine methyl ester pretreatment, the relaxation was significantly inhibited in the two preparations of nonpregnant and pregnant rodents. The relaxation was not inhibited by indomethacin in any of the aortic segments from pregnant and nonpregnant rats. After cytochrome P450 arachidonic acid metabolism inhibitor clotrimazole, a nonsignificant decrease in the Emax to acetylcholine-induced relaxation was observed in the thoracic segments of pregnant and nonpregnant rats. On the other hand, in abdominal aorta, clotrimazole decreased maximal relaxation in rings from pregnant rats (P<.05) but did not change the acetylcholine-induced relaxation from nonpregnant rats. Our results show an increase in the acetylcholine-stimulated release of nitrites in thoracic aortic rings from pregnant rats compared with rings from nonpregnant rats, which cannot be evidenced in abdominal aortic rings. These results suggest that acetylcholine-induced vasodilation in the abdominal segment from pregnant rats is mediated only in part by nitric oxide, the remainder apparently due to an endothelium-derived vasodilator, cytochrome P450-dependent, which may be endothelium-derived hyperpolarizing factor/epoxyeicosatrienoic acid.
Key Words: pregnancy • rats • aorta • nitric oxide • endothelium-derived factors
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Introduction |
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The response of vascular smooth muscle to a variety of vasoactive agents is altered during pregnancy.1 Pregnancy is characterized by a blunted pressor and vasocontractile response to vasoactive substances in women2 3 and in other mammals, such as the rat.4 5 This physiological adaptation seems to account for the observed decrease in blood pressure in the mid-gestation in humans1 and on the days before partum in the rat.6 A decrease in blood pressure is observed during pregnancy, even though cardiac output, total blood volume,1 plasma renin concentration, and renin activity7 are increased. The mechanisms by which these cardiovascular physiological changes occur during pregnancy have long been an object of study, especially since failure to make such adjustments appears to be the basis for the most common complication of pregnancy: preeclampsia.
There is evidence that pregnancy-attenuated response to vasoconstrictors may vary depending on the vascular territory under study. Thus, for example, the influence of pregnancy has been observed in the uterine but not in the carotid artery of guinea pigs.8 Furthermore, it has been shown that the regional variation in the response of the guinea pig thoracic aorta to contractile agonists is augmented during pregnancy.9 The distribution of estrogen receptors has been identified in the baboon thoracic aorta, with an increasing concentration moving proximal to distal.10 Therefore, since the distribution of estrogen receptors may be regionalized, the regional variation in the response of aorta (and other vessels) to contractile agonists could be related to differential sensibility to the hormonal influence associated with, or independent of, the specific mechanisms that reflect the interaction between smooth muscle activation and the release of endothelial substances.
Increased basal release of NO secondary to elevated estrogen plasma concentrations has been proposed as the major mechanism responsible of the cardiovascular changes observed during pregnancy,11 12 but this assumption has not been fully demonstrated,13 and other mechanisms involved have also been proposed.14 Specifically, considering that physiological (or pathological) alterations in endothelial function can be characterized, at least in part, as attenuated or enhanced production and release of other EDRFs than NO, such as PGI2 and EDHF, the participation of the latter two factors in pregnancy-dependent cardiovascular changes needs to be thoroughly evaluated.
We have observed a more remarkable influence of pregnancy in the response to methoxamine in the abdominal compared with the thoracic segments of the rat aorta.15 However, NO mediation of the attenuated response to methoxamine was demonstrated in the thoracic aortic segment but could not be sustained in the abdominal aortic segment. Thus, the mediator responsible for the attenuated contractile response (to vasoactive substances) of the abdominal rat aorta during pregnancy still requires elucidation. Accordingly, the present studies were undertaken to investigate the participation of endothelium-derived vasorelaxant substances on the vascular responses of the thoracic and abdominal aorta from pregnant and nonpregnant rats.
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Methods |
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All experiments were performed with aortic vascular tissue prepared from pregnant in late gestation (day 19 to 21) and nonpregnant age-matched Wistar-Kyoto rats. Standard laboratory rat chow (Purina Mills) and tap water were provided ad libitum. Body weight of the animals at the time of experimentation was 200 to 240 g before pregnancy. Pregnancy was obtained by mating female rats during estrus phase. The day on which spermatozoa were found in the vaginal smear was labeled day 1 of pregnancy.
After slight anesthesia with ether, rats were killed by a blow on the head. Immediately, a midline abdominal and thoracic laparotomy was performed, and the entire descending aorta was excised and placed in iced oxygenated Krebs solution composed of the following (in mmol/L): NaCl 118, KCl 4.8, KH2PO4 1.2, MgSO4.7H2O 1.2, CaCl2.2H2O 2.5, NaHCO3 25.0, dextrose 11.7, calcium disodium EDTA 0.026,16 and propranolol (10-5 mol/L). The specimens were cleaned of adherent fat and adjacent connective tissues. Using the diaphragm as a reference point, two 5-mm-long aortic segments proximal and distal to it were removed and discarded. The remaining portions of either the thoracic or abdominal aorta were cut into equal rings, approximately 5 mm in length. Two rings from each aortic segment were used in each experiment. For isometric tension measurement, each ring was threaded onto two nichrome hooks and suspended between a stationary support at the bottom of the chamber and an isometric force transducer (Statham FT03) connected to a 7D Grass polygraph (Quincy). Rings were placed in an isolated organ chamber of 10-mL capacity containing warmed (37°C), pH 7.4 Krebs buffer aerated with 95% O2/5% CO2. Based on KCl preliminary experiments, the rings were stretched to a basal 3 and 2 g (thoracic and abdominal aorta rings, respectively). Afterwards, responses to phenylephrine (10-7 mol/L) were obtained every 20 minutes until maximal reactivity was observed (usually 2 hours). The functional integrity of the endothelium was pharmacologically assessed by an immediate relaxation induced by ACh (10-6 mol/L) in rings contracted by phenylephrine (10-6 mol/L).
Experimental Protocols
Cumulative concentration-response curves to acetylcholine
(10-9 to 10-4
mol/L) were done in aorta rings from pregnant and nonpregnant
rats submaximally contracted with phenylephrine
(10-6 mol/L). To determine the
participation of NO in ACh-induced relaxation, aortic rings were
pretreated with a selective NO synthase (NOS) inhibitor,
L-NAME (10-5
mol/L)17 for 30 minutes prior to ACh
concentration-response measurements. To determine the effect of
cyclooxygenase products on ACh-stimulated
relaxation, the aortic rings (as above) were pretreated for 30 minutes
with 10-5 mol/L
indomethacin, a concentration previously reported to
effectively inhibit cyclooxygenase18
before the concentration-response curve to ACh. Finally, to evaluate
the contribution of cytochrome P450 (cyt P450)–derived
arachidonic acid metabolites on pregnancy-increased
endothelium-dependent relaxation, ACh
concentration-response measurements were repeated in aortic rings
pretreated (30 minutes) with clotrimazole
(10-5 mol/L). Clotrimazole is
considered to effectively inhibit endothelium-dependent
hyperpolarization at the concentration used in this
work.19 36 In all experiments, one preparation was run in
parallel with the experimental tissues, but received no enzymatic
inhibitor drug, and was used to determine any
time-dependent changes in agonist sensitivity.
Determination of Nitrites (NO2-)
Aortas were obtained from pregnant (day 19 to 21) and
nonpregnant rats (n=5 for each group), separated into thoracic and
abdominal segments, and cut into rings 3 to 4 mm in length
(approximately 8 rings per segment). Each group of rings was incubated
separately in 5 mL of Krebs-bicarbonate solution at 37°C in a shaking
water bath. The solution was changed every 15 minutes until all blood
elements were eliminated (30 to 45 minutes). After this procedure,
groups of rings were incubated (for 30 minutes at 37°C) in a shaking
water bath containing either acetylcholine
(10-4 mol/L) in a total volume of 1 mL
of Krebs (treatment groups) or an equal volume of Krebs in control
groups. At the end of this period, two 500-µL aliquots of the
solution were removed. Duplicate samples were incubated with 40 µL of
a variant of Griess reagent (20 µL trichloroacetic acid 50%, 10 µL
procainamide 2%, and 10 µL N-N naftiletilendiamine 1% in
water) to form a stable azo-dye, which was measured by
spectrophotometry at 548 nm. Nitrites were determined by interpolating
average absorbance values in a standard curve. This assay detects
nitrites in the range 10-7 to
10-4 mol/L. Rings were dried at 60°C
in an oven for 1 hour, and the dry weight was calculated. Data obtained
are expressed as mol · mg-1 · 30
min-1.
Drugs
Fresh solutions of the following drugs were prepared for each
experiment: L-phenylephrine acetylcholine, L-NAME,
clotrimazole, procainamide, and N-N naftiletilendiamine
(all from Sigma Chemical Co). All drugs were dissolved in distilled
water (stock solutions), and dilutions were prepared with Krebs
solution. Sodium carbonate 3.5% was used to bring
indomethacin into solution. All drug concentrations are
expressed as the final molar concentration in the organ
chamber.
Data Analysis
At least 8 animals were included in each experimental group.
Data are expressed as mean±SEM. Vasorelaxation evoked by acetylcholine
is expressed as percent inhibition of the contraction evoked by
predetermined doses of phenylephrine (see above).
Concentrations of ACh producing half-maximal inhibition of the
phenylephrine contractile effect (IC50) and
maximum relaxation effect were estimated by linear regression
analysis (fitted to the Hill equation) from log
concentration-response curves and expressed as -log IC50
and percent of maximal relaxation. Statistical evaluation of the data
was carried out by two-way ANOVA with Bonferroni’s t test
for multiple comparisons and Student’s t test. In all
comparisons, values of P<.05 were considered to indicate
significant differences between or among the means.
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Results |
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ACh produced a concentration-dependent relaxation of rings from rat aortic thoracic or abdominal segments in tissues coming from pregnant and nonpregnant rats (Fig 1). However, ACh-induced relaxation was increased in the rings from pregnant rats compared with the effect observed on rings from nonpregnant animals. Indeed, the ACh EC50 values were lower in the thoracic aorta rings from pregnant than nonpregnant rats (0.10[±0.01]x10-6 mol/L and 0.64[±0.05]x10-6 mol/L, respectively; P<.05). When similar comparisons were evaluated in the abdominal segments, values from pregnant animals were also lower but not significantly different (0.20[±0.05]x10-6 µmol/L and 0.39[±0.10]x10-6 µmol/L, respectively). Although maximal relaxation was similar in the thoracic segment of pregnant and nonpregnant rats (109.3[±9.0]% and 94.4[±7.2]%, respectively), ACh-induced relaxation was increased in the abdominal aortic rings from pregnant rats compared with the effect on rings from nonpregnant rats (110.4[±7.5]% and 84.0[±8.7]%, respectively; P<.05).
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)
and pregnant (•) rats. Data are expressed as percent relaxation of
contraction evoked by phenylephrine
(10-6 mol/L). Each point represents
mean±SEM of 8 to 10 experiments. *P<.05 when compared with
pregnant rats.After incubation of the rings with the NOS inhibitor L-NAME (10-5 mol/L)17 for 30 minutes, ACh-induced relaxation was significantly impaired in both aortic segments from pregnant and nonpregnant rats. However, L-NAME inhibition of ACh-induced relaxation showed important differences depending on the aortic segment or the pregnancy status, ie, ACh maximum relaxation in the presence of L-NAME was reduced to 15.6[±6.3]% and -4.3[±2.5]% (P<.05) in the thoracic aortic rings from nonpregnant and pregnant rats, respectively (Fig 2), whereas ACh-induced maximum relaxation in the presence of L-NAME was 25.3[±4.8]% (pregnant) and 45.0[±11.2]% (nonpregnant) (P<.05) in the abdominal aortic segment (Fig 3).
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), or
indomethacin (10-5 mol/L;
). Data are expressed as percent relaxation of contraction
evoked by phenylephrine (10-6
mol/L) in 8 to 10 experiments. Each point represents mean±SEM
values. *P<.05 when compared with vehicle.
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To further support the relative NO participation in the ACh-induced relaxation, we evaluated vascular NO production by measuring in vitro release of nitrites from abdominal or thoracic aortic rings coming from pregnant and nonpregnant rats. As seen in Fig 4, basal nitrite production was higher in the rings from pregnant rats in both segments, thoracic and abdominal. Values obtained were 0.39[±0.01] and 0.24[±0.02]x10-6 mol · mg-1 · 30 min-1, pregnant and nonpregnant, respectively, in the thoracic aorta (P<.05). For the abdominal segment, values were 0.29[±0.06] and 0.13[±0.02]x 10 -6 mol · mg-1 · 30 min-1 for pregnant and nonpregnant rats, respectively, even when these data did not attain statistical significance.
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When arteries were stimulated with 10-5 mol/L ACh, differences in the nitrite production were evident. In the thoracic segment, aortic rings from the pregnant rats released increased amounts of NO2- (0.75[±0.04]x10-6 mol · mg-1 · 30 min-1) compared with aortas from the nonpregnant animals (0.54[±0.02]x10-6 mol · mg-1 · 30 min-1) (P>.05). However, ACh stimulation of rings from the abdominal aortic segment did not show differences in nitrite production when comparing rings from pregnant and nonpregnant animals (0.42[±0.07] and 0.39[±0.08]x10-6 mol · mg-1 · 30 min-1, respectively) (Fig 4).
We explored PGI2 participation by incubating the arteries with the cylooxygenase inhibitor indomethacin (10-5 mol/L). As seen in Fig 2, cyclooxygenase inhibition in the thoracic aortic rings by indomethacin did not affect ACh-induced relaxation in the rings from pregnant and nonpregnant rats. Similar results were observed in the aortic rings from the abdominal segment (Fig 3).
Cytochrome P450 AA metabolism inhibition by clotrimazole (10-5 mol/L) did not affect ACh-induced maximal relaxation of the abdominal or thoracic aortic rings from nonpregnant rats. Also, relaxation of thoracic rings from pregnant animals was not affected (Figs 2 and 3). By contrast, clotrimazole presence significantly decreased maximal relaxation in the abdominal aorta rings from pregnant animals (110.5[±7.4]% and 73.0[±3.1]% control and clotrimazole-treated, respectively; P<.05) without significantly changing the acetylcholine EC50 (0.20[±0.05]x10-6 mol/L and 0.41[±0.10]x106 mol/L control and clotrimazole-treated, respectively). Additionally, clotrimazole pretreatment modified ACh EC50 values in the thoracic segment of pregnant rats, with values of 0.10[±0.01]x10-6 µmol/L and 0.74[±0.14] x10-6 µmol/L (P<.05) for control and clotrimazole-treated rats, respectively.
Moreover, the combination of clotrimazole and L-NAME totally (96.5%) prevented ACh-induced vasorelaxation in all arteries tested.
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Discussion |
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The aim of this study was to evaluate the possible involvement of EDRFs NO, PGI2, and EDHF in pregnancy-modified relaxation response to ACh in two different segments (abdominal and thoracic) of the rat aorta. The animals were studied in day 19 to 21 of gestation at a time when their basal blood pressure is consistently lower than in controls.
We found that pregnancy enhances ACh-induced relaxation of the thoracic and abdominal rat aorta. This effect of pregnancy has been reported on the uterine, mesenteric, and carotid arteries of guinea pigs and is explained as being a result of increased synthesis and release of EDRF/NO.8 11 Although there is some evidence that appears to implicate increased NO biosynthesis as a key mechanism of gestational vasodilation, other studies fail to support this notion. For example, it has been reported that basal cGMP synthesis is not different between aortas from gravid and virgin rats.20 In addition, NO synthase inhibition failed to augment vasoconstrictor responses to a greater extent in small mesenteric arteries from gravid rats; thus, it was concluded that basal NO synthesis is not increased during pregnancy in the resistance vessels.21 22
In support of NO involvement, our data show that L-NAME pretreatment abolished the relaxation induced by ACh in the thoracic aorta of pregnant and nonpregnant rats. Actually, a contractile effect of ACh in the vessels from pregnant animals was noticed, suggesting that NO is the main mediator of ACh relaxation effect in this aortic segment. On the other hand, the inhibitory effect of L-NAME was less evident in the abdominal segment of pregnant and nonpregnant rats, implying a segmental aortic difference in the mechanisms responsible for the endothelium-derived relaxation.
Basal release of NO measured as total nitrites was higher in the thoracic than in the abdominal segment of the aorta from pregnant and nonpregnant rats, respectively. Specifically, basal release of nitrites from gestating animals aortas was significantly higher than that from nonpregnant rats (Fig 4). Our results are consistent with the report of Conrad et al,23 24 who found increased nitrite excretion and increased urinary and circulating cGMP during gestation. Interestingly, ACh-stimulated nitrite release was significantly increased in the thoracic aorta rings from gravid rats compared with the production of the nonpregnant animals, but such a difference could not be seen in the abdominal rings during pregnancy (Fig 4), which gives support to the hypothesis of different endothelium-derived mediators between thoracic and abdominal segments of the rat aorta.
The role of endogenous prostaglandins in pregnancy has been extensively studied in humans and animals. It has been suggested that vasodilator prostaglandins may oppose the action of vasoconstrictors,25 but other investigators have obtained conflicting results. Paller et al26 showed that treatment with meclofenamate reversed the blunted norepinephrine pressor response in pregnant rats, but this could not be reproduced by Conrad et al with indomethacin or meclofenamate pretreatment.27 In our study, aortic rings incubated with indomethacin produced no significant differences in the concentration-response curves to ACh. It seems therefore that PGI2 (or another vasodilator eicosanoid) participation does not explain the augmented sensibility to ACh displayed by the aortic rings (neither thoracic nor abdominal) from pregnant rats.
Our findings suggest that an endothelium-derived vasorelaxant substance(s) other than PGI2 or NO is participating in the effects of ACh in the abdominal segment compared with the thoracic one, and this points to regionalized differences in the mechanisms of relaxation of this conduit vessel. Our results are consistent with the findings of Zygmunt et al,28 who found evidence of the existence of an endothelium-dependent relaxant pathway distinct from NO in the rat hepatic and aorta arteries. In this way, the increased (L-NAME resistant) relaxation in the abdominal aortic segments from pregnant rats may be related to a greater participation of an EDRF distinct from NO (and PGI2), probably—by exclusion—the EDHF.
Regional variations in the response of the rabbit thoracic aorta to contractile agonists have previously been reported.29 30 Recently, Gregg et al9 reported regionalization of endothelium-dependent relaxation in the thoracic aorta of pregnant and nonpregnant guinea pigs. These authors attribute such variations along the length of the aorta to either differences in muscarinic receptor number or affinity or differences in the receptor transduction system. Also, the rat aorta has shown differences in the activity of reticulum sarcoplasmic Ca2+ transport rate between the thoracic and abdominal segment.31 These findings may indicate differences in metabolic or mechanical properties of the two segments of the artery traditionally considered as a conduit unit.
As mentioned before, an increase in the generation of endothelium-derived vasorelaxant substances other than NO or prostaglandins could explain, in part, the increased response to ACh and contribute to the vasodilatation seen in pregnancy. Unidentified mechanisms other than prostaglandins or NO have been postulated to account for the decreased responses to vasoconstrictors during pregnancy.12 Our results show a decrease in ACh-induced relaxation during pregnancy in aortic rings incubated with the cyt P450 enzyme inhibitor clotrimazole. This effect was more evident in the abdominal compared with the thoracic aortic rings of pregnant rats. The latter suggests that a cyt P450–derived epoxide may be participating to a higher degree in the pregnancy vascular changes observed in the abdominal segment. Many studies have implicated the involvement of cyt P450 enzymes in endothelium-dependent relaxation.32 These enzymes are capable of generating potent vasorelaxant products such as epoxyeicosatrienoic acids (EETs) from arachidonic acid.33 EETs elicit a potent vasodilatory effect and can be synthesized in endothelial cells,34 so it has been recently suggested that EDHF may be a cyt P450–derived epoxide such as EETs.33 Actually, previous studies with pulmonary and aorta arteries of the rat proved that membrane hyperpolarization accounts for 20% to 25% of the relaxation by ACh of noradrenaline-induced tone,35 and, in addition, it has been shown that endothelium-dependent hyperpolarization to ACh is significantly diminished by cyt P450 inhibitors such as clotrimazole.32 36
On the other hand, Chen et al36 observed that endothelium-dependent hyperpolarization to ACh was obtained only at high levels of ACh stimulation in rat mesenteric arteries in which the cyt P450 enzyme activity was induced. In agreement with this observation, results from the present study show an effect of clotrimazole only at the higher ACh concentrations (Figs 2 and 3). Since modulation of cyt P450 enzyme activities results in changes in endothelium-dependent relaxation,36 and cyt P450 activity can be influenced by the hormonal environment during pregnancy,37 38 the results obtained in this study are highly suggestive that at least partially, and in a regionalized manner, pregnancy-dependent responses to ACh are mediated by cyt P450–derived EDHF/EETs.
In summary, the present study using thoracic and abdominal aortic rings from pregnant and nonpregnant rats suggests that ACh-induced, endothelium-dependent vasodilation in the abdominal segment is mediated only in part by NO, the remainder apparently due to an endothelium-derived hyperpolarizing vasodilator, cyt P450–dependent via metabolism of arachidonic acid, which may be EDHF/EET. Furthermore, our data suggest that pregnancy enhanced the stimulated release of this factor from abdominal aorta. On the contrary, the agonist-stimulated release of endothelium-derived NO is a more important regulatory factor in the thoracic segments. This study confirms that the increase in thoracic aorta ACh relaxation from pregnant animals seems to be first mediated by NO. Endogenous prostaglandins do not appear to be involved in the increased vascular responses to ACh in pregnant rats.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was partially supported by a COFAA grant.
Received March 18, 1997; first decision April 24, 1997; accepted May 12, 1997.
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References |
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