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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2435.)
© 2005 American Heart Association, Inc.

Thrombosis

Angiotensin-Converting Enzyme Inhibition Increases Basal Vascular Tissue Plasminogen Activator Release in Women But Not in Men

Mias Pretorius; James M. Luther; Laine J. Murphey; Douglas E. Vaughan; Nancy J. Brown

From Veterans Affairs Medical Center (M.P., D.E.V.), Department of Anesthesiology (M.P.), the Divisions of Clinical Pharmacology (J.M.L., L.J.M., N.J.B.) and Cardiovascular Medicine (D.E.V.), Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Mias Pretorius, MBChB, MSc, 560 RRB, Vanderbilt University Medical Center, Nashville, TN 37232. E-mail mias.pretorius{at}vanderbilt.edu

	Abstract

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Objective— Angiotensin-converting enzyme inhibition (ACEI) increases vascular tissue plasminogen activator (t-PA) release through endogenous bradykinin (BK). We tested the hypothesis that gender influences the effect of ACEI on t-PA release.

Methods and Results— We measured the effect of intra-arterial enalaprilat (0.33 µg/min per 100 mL forearm volume) on forearm blood flow (FBF) and net t-PA release before and during BK (25 to 400 ng/min) and methacholine (3.2 to 12.8 µg/min) in premenopausal women, postmenopausal women not using hormone replacement, young men, and older men. Baseline net t-PA release was similar among groups. Enalaprilat increased basal t-PA release in premenopausal (from 0.9±1.0 to 5.1±1.7 ng/min per 100 mL, P=0.023) and postmenopausal women (from –3.9±2.2 to 3.9±1.1 ng/min per 100 mL, P=0.010) but not in young or older men (P=0.028 men versus women). Enalaprilat potentiated the effect of exogenous BK on FBF similarly in all groups. However, during enalaprilat, BK-stimulated t-PA release was greatest in premenopausal women (339.9±86.4 ng/min per 100 mL at the 100 ng/min dose, P<0.05 versus any other group), intermediate in postmenopausal women (243.8±51.1 ng/min per 100 mL, P<0.05 versus either male group), and least in young (111.9±19.2 ng/min/100 mL) and older men (103.4±27.6 ng/min/100 mL).

Conclusion— ACEI enhances basal t-PA release in women, independent of menopausal status, but not in men. During ACEI, both gender and menopausal status affect BK stimulated t-PA release.

This study tests the hypothesis that gender influences the effect of ACE inhibition on vascular t-PA release. Enalaprilat increased basal t-PA release in premenopausal (P=0.023) and postmenopausal women (P=0.010) but not in young or older men. During enalaprilat, basal t-PA release was significantly greater in women compared with men (P=0.028).

Key Words: angiotensin • inhibitors • plasminogen activators • women

	Introduction

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Angiotensin-converting enzyme (ACE) inhibition improves endothelial function¹ and favorably alters fibrinolytic balance by decreasing angiotensin II (Ang II), a potent stimulus to plasminogen activator inhibitor-1 (PAI-1) synthesis^2–4 and by increasing bradykinin (BK), a potent stimulus to tissue plasminogen activator (t-PA) secretion.^5,6 For example, a recent study from this group using the specific BK B₂ receptor antagonist HOE 140 indicates that ACE inhibition increases baseline vascular t-PA release in humans through endogenous BK.⁷ Unexpectedly, ACE inhibition increased basal t-PA release only in the female subjects studied. Moreover, ACE inhibition did not increase basal t-PA release in 2 earlier studies in predominantly male populations.^5,8

Coronary BK concentrations increase during myocardial ischemia⁹ and ACE inhibitors potentiate BK-stimulated coronary⁸ as well as forearm t-PA release.⁵ Thus BK-stimulated t-PA release may be important in limiting thrombosis during myocardial infarction. Whereas the previous data of Pretorius et al⁷ suggested that gender influences the effect of ACE inhibition on basal t-PA release, that study was not designed to test such a hypothesis. Study groups were not prospectively matched for gender. More importantly, the dose of enalaprilat was not normalized per forearm volume. Thus women, who have a smaller forearm volume than men, were given a higher effective dose of ACE inhibitor. For these reasons, the present study was prospectively designed to test the hypothesis that ACE inhibition has a greater effect on endothelial t-PA release in women than in men. In addition, to determine whether any effect of gender on t-PA release was estrogen-mediated, we studied premenopausal women and postmenopausal women not taking hormone replacement therapy (HRT).

	Methods

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Subjects
Thirty-two healthy volunteers (8 premenopausal women, 8 postmenopausal women, 8 young men, and 8 older men) participated in the study. Premenopausal women were studied in the luteal phase of their menstrual cycle. Two premenopausal women were taking hormone contraceptives. Women were defined as postmenopausal if it had been at least 1 year since their last menstruation. None of the postmenopausal women used hormone replacement therapy (HRT) for at least 1 month before the study date. After written informed consent was obtained, all subjects underwent a complete history and physical examination, and an ECG and routine laboratory were obtained. Subjects with significant cardiovascular, renal, pulmonary, endocrine, or hematologic disease were excluded. All subjects were within 30% of their ideal body weight. Pregnancy was excluded in women of childbearing potential by measurement of urine ß-hcg. Subjects with a fasting cholesterol >5.7 mmol/L (220 mg/dL) and smokers were excluded.

Experimental Protocol
The study protocol was approved by the Vanderbilt University Institutional Review Board and conducted according to the Declaration of Helsinki. Studies were performed in the morning in a temperature-controlled room (http://atvb.ahajournals.org). After placement of arterial and venous catheters, subjects were allowed to rest 30 minutes before baseline measurements were made. After measurement of baseline forearm blood flow (FBF) and blood sampling, graded doses of sodium nitroprusside (SNP) (endothelium-independent control) at 1.6, 3.2, and 6.4 µg/min; methacholine (MCH) (endothelium-dependent, bradykinin-receptor independent control) at 3.2, 6.4, and 12.8 µg/min; and BK at 100, 200, and 400 ng/min were infused in the brachial artery in random order. Each dose was infused for 5 minutes and FBF was measured during the last 2 minutes.

Thirty minutes after administration of these three drugs, baseline measurements were repeated and subjects then received a continuous intra-arterial infusion of enalaprilat at 0.33 µg/min per 100 mL forearm volume. While continuing enalaprilat, baseline measurements and infusions of MCH and BK were repeated. BK doses were reduced to 25, 50 and 100 ng/min during enalaprilat because two subjects in a prior study developed transient arm swelling after infusion of BK in the presence of enalaprilat.⁷ Forearm perfusion measurements were performed as previously published (http://atvb.ahajournals.org).

Blood Sampling and Biochemical Assays
After measurement of FBF, simultaneous arterial and venous samples were obtained from the infused arm before and after each dose of MCH and BK. Because numerous studies have demonstrated that SNP does not increase net t-PA release,^5,10–12 no blood was drawn during SNP. Blood samples were collected on ice and centrifuged immediately, and plasma was stored at –70°C until the time of assay. Blood for measurement of t-PA and PAI-1 was collected in tubes containing 0.105 mol/L acidified sodium citrate, PAI-1 and t-PA antigen levels were determined using a 2-site enzyme-linked immunosorbent assay (Biopool AB). t-PA activity was not measured, as we have demonstrated previously that active t-PA increases with t-PA antigen during BK infusion.¹²

Forearm plasma flow was calculated from the FBF and arterial hematocrit corrected for 1% trapped plasma. Thus, individual net release or uptake rates at each time point were calculated by the following formula: net release=(C_v–C_A) x{FBF x [101–hematocrit/100]}, where C_v and C_A represent the concentration of t-PA or PAI-1 in the brachial vein and artery, respectively.

Serum ACE activity was determined by an enzymatic method (Fujirebio America Inc, Fairfield, NJ). Blood for measurement of BK and its degradation product, BK1–5, was drawn into cold anhydrous ethanol and centrifuged after 1 hour; the supernatant was saved at –70°C until the time of assay. BK1–5 was determined using a dual-isotope dilution mass spectrometric assay as previously described.¹³ BK was determined using a commercially available enzyme immunoassay (Peninsula Laboratories, Inc Division of Bachem, San Carlos, Calif).

Statistical Analysis
Data are presented as means±SEM. Categorical data were compared using ² or Fischer exact tests, as appropriate. For continuous variables, baseline data were compared among groups using one-way (analysis of variance) ANOVA with post hoc comparisons or Mann-Whitney U test as appropriate. BK and BK1–5 data were log-transformed before analysis. The effect of agonists on hemodynamic and fibrinolytic variables were determined using a general linear model-repeated measures ANOVA in which the between-subject variables were gender, menopausal status, and quartiles of age, and cholesterol or mean arterial pressure (MAP), the within-subjects variables were the dose and the presence or absence of enalaprilat. Within groups, the effect of enalaprilat on the FBF or t-PA response to 100 ng/min BK was determined using a paired t-test. To determine whether gender or menopausal status affected sensitivity to exogenous BK, SNP, or MCH, we constructed individual dose response curves in which agonist dose was first corrected for forearm volume and then log transformed. The slopes of these individual curves were then compared among groups, controlling for potential confounding factors such as cholesterol. A 2-tailed P<0.05 was considered statistically significant. Statistical analysis were performed with the statistical package SPSS for Windows (Version 12.0; SPSS, Chicago, Ill and GraphPad Prism for Windows (Version 4.0; GraphPad, San Diego, Calif)

	Results

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Subject Characteristics
Table I (available online at http://atvb.ahajournals.org) provides the baseline clinical characteristics of the subjects. There were no significant differences among premenopausal women, postmenopausal women, young men, and older men with regard to ethnicity, body mass index or heart rate. As predefined, postmenopausal women and older men were significantly older than the premenopausal women and young men studied. Serum cholesterol was significantly lower in premenopausal women compared with older men, but similar in postmenopausal women and older men.

Effect of Enalaprilat, Gender, and Menopausal Status on ACE Activity, MAP, Resting FBF, FVR Net t-PA, and PAI-1 Release
Table 1 provides the effect of intra-arterial enalaprilat on ACE activity and resting FBF in the 4 study groups. Although baseline ACE activity tended to be lower in premenopausal women compared with the other 3 groups, this difference did not reach statistical significance. Enalaprilat significantly decreased ACE activity in all study groups; however, during enalaprilat, ACE activity was significantly lower in postmenopausal women and older men compared with premenopausal women or young men.

View this table: [in this window] [in a new window]   TABLE 1. Effect of Enalaprilat on MAP, FBF, FVR, and ACE Activity

MAP was significantly lower in the premenopausal women compared with older men. There was no effect of intra-arterial enalaprilat on MAP in any group. Similarly, there was no effect of enalaprilat on FBF in any study group. Enalaprilat significantly decreased FVR in postmenopausal women (P=0.019) but not in premenopausal women, young men, or older men.

Baseline net t-PA release was statistically similar in premenopausal women, postmenopausal women, young men and older men (P=0.111, Figure 1). Enalaprilat significantly increased basal net t-PA release in both premenopausal (from 0.9±1.0 to 5.1±1.7 ng/min per 100 mL, P=0.023) and postmenopausal women (from –3.9±2.2 to 3.9±1.1 ng/min per 100 mL, P=0.010) but not in young men (from –0.1±1.3 to 1.3±1.4 ng/min per 100 mL, P=0.142) or older men (from 0.03±0.9 to 0.7±1.9 ng/min per 100 mL, P=0.766). Thus, during enalaprilat, basal t-PA release was significantly greater in women compared with men (P=0.028). There was no effect of age, cholesterol or MAP on resting FBF, FVR, or net t-PA release. Baseline PAI-1 antigen concentrations and net PAI-1 release were statistically similar in all groups (all P>0.208). Enalaprilat had no effect on net PAI-1 extraction in any group (all P>0.099; Table II, available online at http://atvb.ahajournals.org). Net PAI-1 extraction was not statistically different between women and men in the presence of enalaprilat (–1.8±2.0 versus –0.5±0.7 ng/min per 100 mL respectively, P=0.568). In addition, there was no effect of age, cholesterol, or MAP on resting net PAI-1 release.

View larger version (22K): [in this window] [in a new window]   Figure 1. The effect of enalaprilat on basal t-PA release in premenopausal women, postmenopausal women, young men, and older men. *P<0.05 vs baseline. P=0.028 for all women vs men during enalaprilat.

Effect of Enalaprilat, Gender, and Menopausal Status on FBF and t-PA Response to Exogenous BK
To determine whether gender and menopausal status affected sensitivity to BK, we compared the response to exogenous BK in premenopausal women, postmenopausal women, young men, and older men in the presence and absence of enalaprilat. Local intra-arterial infusion of BK did not affect MAP in any group in the absence or presence of enalaprilat; therefore data are presented as FBF. As illustrated in Figure 2, BK increased FBF in a dose-dependent manner (all P<0.014) and enalaprilat potentiated this effect in all four study groups. Thus, the FBF response to 100 ng/min BK was 2.2-fold higher in premenopausal women (27.4±2.4 versus 12.3±1.6 mL/min/100 mL, P=0.004), 1.8-fold higher in postmenopausal women (27.6±3.8 versus 15.2±2.6 mL/min per 100 mL, P=0.003), 1.8-fold higher in young men (24.3±2.9 versus 13.4±1.8 mL/min per 100 mL, P=0.003), and 1.8-fold higher in old men (20.1±2.1 versus 11.4±2.3 mL/min per 100 mL, P=0.007) during enalaprilat. There was no effect of gender or menopausal status on the relationship between BK dose and FBF in the absence or presence of enalaprilat.

View larger version (19K): [in this window] [in a new window]   Figure 2. The effect of enalaprilat on the forearm blood flow (FBF) response to bradykinin in premenopausal women (A), postmenopausal women (B), young men (C), and older men (D). Bradykinin dose was corrected for forearm volume for each subject. The double standard error bars reflect the variability in FBF and forearm volume corrected dose.

As illustrated in Figure 3, BK also increased net t-PA release in a dose-dependent fashion in premenopausal women (P=0.018), postmenopausal women (P=0.021), young men (P=0.035), and older men (P=0.007). Enalaprilat significantly potentiated the effect of BK on t-PA release in all 4 groups. For example, enalaprilat increased net t-PA release in response to 100 ng/min BK from 23.9±4.4 to 339.9±86.4 ng/min per 100 mL in premenopausal women (P=0.007), from 7.0±7.1 to 243.8±51.1 ng/min per 100 mL in postmenopausal women (P=0.002), from 15.7±7.7 to 111.9±19.2 ng/min per 100 mL in young men (P=0.001), and from 4.6±2.5 to 103.4±27.6 ng/min per 100 mL in older men (P=0.007). However, enalaprilat potentiated BK-stimulated t-PA release to a greater extent in premenopausal women than in young men, older men, and postmenopausal women, such that the slope of the relationship between BK dose and net t-PA release (Figure 3) was greatest in premenopausal women (P=0.026 versus young men, P=0.021 versus older men and P=0.024 versus postmenopausal women), intermediate in postmenopausal women (P=0.047 versus young men and P=0.036 versus older men) and least in young and older men during enalaprilat. There was no effect of age, cholesterol, or MAP on BK-stimulated FBF, FVR, or net t-PA release.

View larger version (18K): [in this window] [in a new window]   Figure 3. The effect of enalaprilat on the net t-PA response to bradykinin in premenopausal women (A), postmenopausal women (B), young men (C), and older men (D). Bradykinin dose was corrected for forearm volume for each subject. The double standard error bars reflect the variability in net t-PA release and forearm volume corrected dose.

Effect of Enalaprilat, Gender, and Menopausal Status on BK and BK1–5 Concentrations
Table 2 provides forearm BK, BK1–5 (the stable metabolite of BK degradation by ACE) concentrations and BK1–5:BK ratio during BK (100 ng/min) infusion in the presence and absence of enalaprilat. Concentrations of BK and BK1–5 were similar among the 4 groups at baseline. Baseline BK1–5:BK ratio, an indicator of bradykinin degradation by ACE, was significantly higher in postmenopausal women compared with older men. Enalaprilat significantly enhanced BK concentrations in all 4 groups (4.8-fold average increase; all P<0.008). In addition, enalaprilat significantly decreased BK1–5 (5.2-fold average decrease; all P<0.012) and the BK1–5:BK ratio (all P<0.003) in all 4 groups. During enalaprilat, the BK1-5-to-BK ratio was decreased to a greater extent in postmenopausal women and older men than in premenopausal women.

View this table: [in this window] [in a new window]   TABLE 2. Effect of Enalaprilat on Bradykinin and BK 1–5 Concentrations in Premenopausal Women, Postmenopausal Women, Young Men, and Older Men During Bradykinin Infusion at 100 ng/min

Effect of Enalaprilat, Gender, and Menopausal Status on FBF Response to MCH and SNP and Net t-PA Response to MCH
FVR was used to assess vasodilator responses to SNP because intra-arterial infusion of SNP significantly decreased MAP (P=0.001). After correcting for changes in MAP, there was no effect of gender (P=0.406), menopausal status (P=0.496), cholesterol (P=0.750), or age (P=0.445) on the FVR response to SNP (Table III, available online at http://atvb.ahajournals.org).

Infusion of MCH did not affect MAP. MCH caused a dose-dependent increase in FBF in premenopausal women (P=0.006), postmenopausal women (P=0.003), young men (P=0.022), and older men (P=0.008) (Table IV, available online at http://atvb.ahajournals.org). There was no effect of gender (P=0.718), menopausal status (P=0.817), cholesterol (P=0.965), or age (P=0.462) on the FBF response to MCH. MCH increased net t-PA release in premenopausal women (from 2.3±2.5 to 46.1±11.1 ng/min per 100 mL, P<0.001) and postmenopausal women (from 0.05±0.5 to 25.3±6.0 ng/min per 100 mL, P=0.030) but not in young men (from 2.5±1.2 to 5.8±9.0 ng/min per 100 mL, P=0.809) or older men (from –0.4±1.2 to 1.5±9.0 ng/min per 100 mL, P=0.443) and there was a significant effect of gender (P=0.040) on the t-PA response to MCH. There was no effect of menopausal status (P=0.102), cholesterol (P=0.606) or age (P=0.931) on the net t-PA response to MCH. Enalaprilat did not affect MCH-stimulated FBF (all P>0.141) or t-PA release in any group (All P>0.375).

	Discussion

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Studies have consistently indicated that ACE inhibition potentiates the effect of exogenous BK on t-PA release from the peripheral and coronary vasculature in patients with coronary artery disease or risk factors for coronary artery disease.^5,7,8,14 In contrast, these studies have provided conflicting data as to the effect of ACE inhibition on basal t-PA release.^5,7,8,15 Thus, at least 3 studies have reported no effect of ACE inhibition on basal t-PA release,^5,8,15 whereas Pretorius et al⁷ reported that ACE inhibition increases basal t-PA release through a BK-dependent mechanism. The inclusion of premenopausal women in the Pretorius study but not the others and the post hoc observation that, during ACE inhibition, basal t-PA release was increased in the women but not in the men studied generated the hypothesis that gender influences the effect of ACE inhibition on vascular fibrinolytic function. The present study tests this hypothesis prospectively and confirms that ACE inhibition increases basal t-PA release in women but not in men.

To determine whether hormonal status could have contributed to the effect of gender on basal t-PA release during ACE inhibition, we studied both premenopausal and postmenopausal women. Significantly, basal t-PA release was increased during ACE inhibition in both premenopausal and postmenopausal women. Endothelial t-PA release occurs through both constitutive and regulated pathways. In constitutive release, newly synthesized t-PA is transported directly from the Golgi apparatus to the cell membrane and secreted even in the absence of an extracellular stimulus, whereas, in regulated secretion, stored t-PA is released from its endothelial granules in response to activation of membrane receptors.^16–18 The contribution of constitutive versus regulated t-PA release to the basal level of plasma t-PA is still unresolved. Several lines of investigation, however, suggest that regulated secretion maintains basal plasma t-PA concentrations.^17,19 To the extent that endogenous BK contributes to basal t-PA release during ACE inhibition via its B₂ receptor⁷ and that testosterone decreases BK-induced calcium influx,²⁰ decreased basal t-PA release in men during ACE inhibition may reflect an effect of testosterone on BK signaling.

In contrast to the similar effect of ACE inhibition on basal t-PA release in premenopausal and postmenopausal women, ACE inhibition potentiated exogenous BK-stimulated t-PA release to a greater extent in premenopausal women than in postmenopausal women or men. These data suggest that estrogen status may modulate the potentiation of BK-stimulated t-PA release during ACE inhibition. ACE inhibitors potentiate the effects of BK both by decreasing its degradation and by increasing B₂ receptor sensitivity.^21,22 Estrogen has been shown to decrease ACE activity,²³ to upregulate BK receptors^24,25 and to increase t-PA synthesis in some^26,27 but not all studies.^28,29 To exclude an effect of gender or menopausal status on BK degradation during ACE inhibition, we measured both ACE activity and kinin concentrations and found that differences in BK degradation cannot account for differences in basal or BK-stimulated t-PA release during ACE inhibition.

To determine whether gender or menopausal status influenced sensitivity to BK at the receptor or post-receptor level we compared dose-response curves for the effect of exogenous BK on FBF and t-PA release in the presence and absence of ACE inhibitor. The observation that gender did not affect the BK dose-vasodilation response curve during ACE inhibition suggests that gender and hormonal status influence BK-stimulated t-PA release at a point downstream to the B₂ receptor. In this regard, pharmacologically stimulated t-PA release correlates with t-PA synthesis in vitro and in vivo.¹⁶ Thus, during ACE inhibition, enhanced t-PA release in response to pharmacological doses of BK in premenopausal women compared with postmenopausal women and men may reflect an effect of estrogen to increase intracellular stores of t-PA.^26,27 However, the finding that BK-stimulated t-PA release was also increased in postmenopausal women compared with men and that methacholine-stimulated t-PA release was increased in both premenopausal and postmenopausal women suggests that other factors may affect t-PA synthesis and storage in women.

The results of the current study are compatible with those of 2 previous studies. For example, Hoetzer et al³⁰ reported that BK-stimulated t-PA release was increased in postmenopausal women taking hormone replacement therapy compared with those not taking estrogen. In addition, in that study, acute 17ß-estradiol significantly potentiated BK-induced t-PA release but had no effect on basal t-PA release. Likewise, the lack of effect of hormonal status on MCH-stimulated t-PA release is compatible with work of Jern et al,³¹ who reported no effect of estrogen on MCH-stimulated release of t-PA in postmenopausal women with noninsulin-dependent diabetes.

Although all of the subjects in the present study were normotensive and normocholesterolemic, blood pressure and cholesterol were decreased in the premenopausal women studied compared with other groups. Because hypertension and hypercholesterolemia have been associated with attenuated vasodilation and t-PA responses to endothelium-dependent agonists,^32–34 we cannot exclude an influence of these factors on t-PA release in the premenopausal women. However, in this study in normal subjects, we did not see an effect of blood pressure or cholesterol on basal or BK-stimulated t-PA release when these variables were considered in the analysis. Moreover, whereas relatively increased blood pressure and cholesterol could have been expected to contribute to the attenuated response to exogenous BK in postmenopausal women these factors would also have been expected to diminish basal t-PA release and BK-stimulated vasodilation during ACE inhibition.

In summary, ACE inhibition increased basal t-PA release in both premenopausal and postmenopausal women, whereas ACE inhibition potentiated BK-stimulated t-PA release to a greater extent in premenopausal women compared with either postmenopausal women or men. These data are relevant to recent clinical trials^35,36 examining the cardioprotective effects of ACE inhibitors within gender groups. The current study provides one mechanistic rationale for further studies examining the interactive effects of ACE inhibition and hormone replacement therapy on thrombotic outcomes in women.

	Acknowledgments

 
We are grateful to Tami Neal, RN, for her nursing assistance, and to Jeff Petro, BS and Rhoda Jones, BS, for their technical assistance.

This work was funded by NIH grants HL60906, HL65193, HL67308, HL04445, and RR00095. Dr Pretorius is the recipient of a VA merit review entry program award.

Received May 9, 2005; accepted September 2, 2005.

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