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Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan# t5 \) v9 Q8 h( x7 l2 |- h" B+ h
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ABSTRACT

A high-salt diet increases renal endothelin (ET) production and thick ascending limb (THAL) endothelial nitric oxide synthase (eNOS) expression. ET stimulates THAL eNOS expression via ETB receptors. The tonicity of the renal medulla is highly variable, and hyperosmolality stimulates ET-1 synthesis by endothelial cells. We hypothesized that a high-salt diet raises medullary osmolality, increases ET release by the THAL, and thus enhances eNOS expression. Seven days of high salt (1% NaCl in drinking water) increased eNOS expression in THALs by 125 ± 31%. High salt increased outer medullary osmolality from 362 ± 13 to 423 ± 6 mosmol/kgH2O (P
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nitric oxide; kidney; outer medulla; Henle's loop

NITRIC OXIDE (NO) is produced by both renal endothelial and epithelial cells (16, 18, 26, 32). NO dilates renal blood vessels (1, 18) and inhibits solute and water reabsorption by the nephron (6, 25, 27, 40, 42). When animals are placed on a high-salt diet, expression of all three NO synthase (NOS) isoforms (endothelial, neuronal, and inducible NOS) increases in both the outer and inner medulla (21, 34). The outer medulla is composed primarily of thick ascending limbs (THALs), and we showed that high salt enhances expression of endothelial NOS (eNOS) in this segment (24). However, the mechanisms by which a high-salt diet augments THAL eNOS expression are unknown.7 W% d  c# o7 O% I+ s2 d
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Renal endothelin (ET) production increases when animals are given increased salt (11, 12, 36). The THAL produces ET (14), which exerts its effects via at least two different receptors, ETA and ETB (19). ETB receptors mediate acute stimulation of NO production by eNOS in the THAL (30). Recently, we showed that ET also chronically regulates NO production in this segment by enhancing eNOS expression via ETB receptors (10). However, it is not known whether ET acting via the ETB receptor mediates the increase in eNOS protein induced by a high-salt diet.) ^( P8 M; H% T6 @

The tonicity of the renal medulla is highly variable; it can be either hypotonic or hypertonic, and changes in tonicity alter the expression of many proteins (4). Changes in the osmolality of the renal medulla caused by water loading (23), dehydration (35), and diuretics (39) have been extensively studied. However, it is not clear whether a high-salt diet alters outer medullary tonicity, nor what role changes in tonicity may play in regulating ET release and/or eNOS expression.

We hypothesized that a high-salt diet increases outer medullary osmolality. This increased tonicity enhances ET release by the THAL, and ET acting via the ETB receptor increases eNOS expression in this segment. To test our hypothesis, we measured tissue osmolality and the effects of high salt, osmolality, and ET antagonists on eNOS expression in vivo and in vitro as well as ET release in vitro.' j0 P- v$ w) F: h$ s0 ?# k

MATERIALS AND METHODS; ]9 S2 J5 h4 d: [( W- @0 t

Diet. Male Sprague-Dawley rats weighing 101–125 g (Charles River, Kalamazoo, MI) were fed a diet containing 0.22% sodium and 1.1% potassium (Purina, Richmond, IN). Animals on a "normal" diet drank tap water, whereas animals on the "high-salt" diet drank 1% NaCl for 7 days., h9 R; Z! G! ^% D  R9 d

Medullary THAL suspensions. Sprague-Dawley rats were anesthetized with ketamine (100 mg/kg body wt ip) and xylazine (20 mg/kg body wt ip). The abdominal cavity was opened and the kidneys were flushed with 40 ml of ice-cold 0.1% collagenase in HBSS via retrograde perfusion of the aorta. Kidneys were removed and coronal slices were dissected. The inner stripe of the outer medulla was minced into 1-mm3 fragments and digested in 0.1 mg/ml collagenase at 37°C for 30 min. During each 5-min period, the tissue was gently agitated and gassed with 100% oxygen. After continuous agitation for 30 min in cold HBSS, the tissue was filtered through a 250-μm nylon mesh and rinsed twice with either buffer or culture medium.! R: N$ o  @4 ^/ q1 _

Primary cultures of medullary THALs. THAL suspensions were resuspended in DMEM/F-12 supplemented with 5% heat-inactivated FBS, 20 ng/ml epidermal growth factor (EGF), 100 U/ml penicillin, and 100 μg/ml streptomycin. A total of 50 μl of the cell suspension was lysed and protein concentration was determined. Then, a volume of cell suspension corresponding to 100 μg of total protein was plated in each well of a six-well plate. After 24 h, serum and EGF were removed from the medium for 14 h and cells were treated as indicated in the text. All treatments lasted 24 h. Ninety-two percent of cells in primary cultures were derived from the THAL as evidenced by positive Tamm-Horsfall staining. Hyperosmolar medium was obtained by supplementing serum-free medium with NaCl, urea, or mannitol to achieve the desired osmolality as described in the text. Osmolality was checked by freezing-point depression using a microosmometer (Advanced Products Systems, Norwood, MA).& ]; x) C. R. n( c5 S) e5 R
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Western blot analysis. For all experiments, medullary THAL (mTHAL) suspensions or scraped cells were lysed by vortexing then in a buffer containing 20 mmol/l HEPES (pH 7.4), 2 mmol/l EDTA, 0.3 mol/l sucrose, 1.0% NP-40, 0.1% SDS, 5 μg/ml antipain, 10 μg/ml aprotinin, 5 μg/ml leupeptin, 4 mmol/l benzamidine, 5 μg/ml chymostatin, 5 μg/ml pepstatin A, and 0.105 mol/l pf-block (Sigma, St. Louis, MO). Samples were centrifuged at 6,000 g for 5 min at 4°C and protein content in the supernatant was determined. For a given experiment, equal amounts of total protein were loaded into each lane of an 8% SDS-polyacrylamide gel, separated by electrophoresis, and transferred to a PVDF membrane (Millipore, Bedford, MA). Fresh samples were used because we found that freezing degrades eNOS and leads to multiple bands on Western blotting. The membrane was incubated in blocking buffer containing 50 mmol/l Tris, 500 mmol/l NaCl, 5% nonfat dried milk, and 0.1% Tween 20 for 60 min and then with a 1:1,000 dilution of an eNOS-specific monoclonal antibody (BD Transduction Laboratories, San Diego, CA) in blocking buffer for 60 min at room temperature. The membrane was washed in a buffer containing 50 mmol/l Tris, 500 mmol/l NaCl, and 0.1% Tween 20 and incubated with a 1:1,000 dilution of secondary antibody against the appropriate IgG conjugated to horseradish peroxidase (Amersham Pharmacia Biotech, Arlington Heights, IL). The reaction products were detected with a chemiluminescence kit (Amersham). The signal was detected by exposure to Fuji RX film and quantified by densitometry.

DNA isolation and quantification. A total of 200 μl of mTHAL suspensions from animals fed either a normal- or a high-salt diet was lysed using the same procedure as for Western blot analysis. Total DNA was isolated using a commercial kit (DNeasy, Qiagen, Valencia, CA) according to the manufacturer's instructions. DNA in each sample was quantified by its absorbance at 260 nm./ s) G( f" R7 R4 }9 k# z

Tissue osmolality measurements. After the abdominal cavity was opened, the left kidney was bathed in ice-cold saline, removed, and coronal slices were dissected. A piece of cortex and the inner stripe of the outer medulla (where more than 90% of cells are THAL cells) were minced, weighed, and placed in vials containing 200 μl distilled water. Samples were heated in boiling water for 2 h to destroy tissue urease and extract solutes. Following centrifugation, osmolality in the supernatant was determined by freezing-point depression. The remaining tissue was dried overnight at 40°C in an oven, weighed, and water content was determined. Osmolality of each sample was calculated and related to tissue water content. Results are expressed as mosmol/kgH2O.

Bosentan experiment. Male Sprague-Dawley rats weighing 101–125 g were treated with 100 mg﹞kg–1﹞day–1 bosentan (Ro 47–0203/029, a dual-ET receptor antagonist) or vehicle (5% gum arabic) for 2 days by gastric gavage. On day 2, they were placed on a high-salt diet for 7 days. Bosentan or vehicle was maintained every day during the experiment. On day 9, mTHAL suspensions were obtained and 10 μg total protein from vehicle- and bosentan-treated animals were loaded onto the same 8% polyacrylamide gel. Western blot analysis for eNOS detection was performed as described above.2 R; h% B1 v: D2 [' e9 X& f$ H
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Blood pressure determination. Systolic blood pressure in conscious rats was determined by tail cuff. Bosentan or vehicle was administered to animals fed a high-salt diet as described above. At day 9, animals were maintained at 37°C for 15 min and three consecutive measurements of systolic blood pressure were recorded using a type 502 dual-beam oscilloscope (Tektronix, Portland, OR) connected to an electrosphygmomanometer (Narco Bio-Systems, Houston, TX). Animals were trained each day during the treatment period. The average size of rats by the day of the experiment was between 147 and 175 g.

Protein content determination. Total protein content was determined using Coomassie Plus reagent (Pierce, Rockford, IL), based on Bradford's colorimetric method.3 T. E3 H, ~+ N; r+ L

Measurement of ET-1 release. ET-1 in the culture medium was quantified using an enzyme immunoassay kit from R&D Systems (Minneapolis, MN). Cells were maintained for 48 h in iso and hyperosmolar DMEM/F-12 medium (300 and 400 mosmol/kgH2O, obtained by adding NaCl) supplemented with 5% FBS and 100 KIU/ml aprotinin. Medium was replaced and samples were collected after 1 h. Results are expressed as picograms of ET-1 per milligram of protein per hour.3 `3 s/ _) B4 j. ~! V4 c9 G% U
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Materials. BQ-788 (ETB receptor antagonist) was purchased from Peninsula (Belmont, CA); collagenase, EGF, and gum arabic were obtained from Sigma; DMEM/F-12 medium and HBBS from GIBCO (Carlsbad, CA); and FBS from Hyclone (Logan, UT). Bosentan was kindly supplied by Dr. M. Clozel (Actelion Pharmaceuticals, Switzerland).
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Statistics. Data are reported as means ± SE. They were evaluated by ANOVA for repetitive measurements or paired t-test as appropriate. P - q$ W; W! \& C  K& m2 u' V- }# x1 ~1 u

RESULTS

We first measured eNOS expression in mTHAL suspensions from animals fed a normal- or a high-salt diet. In accord with our previous study (24), we found that 7 days on high salt increased THAL eNOS expression from 1.92 ± 0.44 to 4.44 ± 0.43 O.D. units (P ' F+ V7 R7 z( J" G. k. C

Renal production of the vasoactive peptide ET is increased by high salt (11), and we demonstrated that ET-1 increases eNOS expression in THAL cells in vitro (10). To investigate whether ET mediates the effect of high salt in vivo, we studied the ability of bosentan, a dual-ET receptor antagonist, to block the increase in THAL eNOS expression caused by a high-salt diet. eNOS expression in mTHAL suspensions from animals on high salt increased from 1.92 ± 0.44 absorbance units to 4.44 ± 0.43 (P   D, N; ?* u7 K! g

To determine whether increased tissue osmolality contributes to the enhanced THAL eNOS expression stimulated by high salt, we investigated whether high salt raises the osmolality of the outer medulla, where more than 90% of cells are THAL cells. In animals fed a normal diet, outer medullary osmolality was 362 ± 14 mosmol/kgH2O (n = 5), whereas in animals fed a high-salt diet it increased to 423 ± 6 mosmol/kgH2O (P
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To determine which step in the signaling cascade is affected by bosentan, we investigated its effect on medullary osmolality. To do this, we measured outer medullary osmolality in animals fed a high-salt diet in the presence or absence of bosentan. We found no significant differences between groups, suggesting that stimulation of eNOS expression by high salt is due to activation of ET receptors following an increase in medullary osmolality.. P% |. `: o& s+ [

Because medullary osmolality increased when animals were fed a high-salt diet, we next investigated whether increasing osmolality per se could augment eNOS expression. In primary cultures of mTHALs, raising the osmolality of the medium by 50 and 100 mosmol/kgH2O with NaCl increased eNOS expression by 39 ± 11% (P
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The osmolality of the renal medulla is determined by the presence of different solutes such as NaCl and urea (2). To investigate whether the increase in eNOS expression is solute dependent, we next tested the effect of increasing the osmolality of the medium using different solutes. In our primary cultures of mTHALs, raising the osmolality of the medium to 400 mosmol/kgH2O for 24 h with NaCl, mannitol, or urea increased eNOS expression by 67 ± 16% (P   I+ o( _6 p; ^# B4 r

When animals are fed a high-salt diet, urinary ET levels increase, indicating elevated production of ET-1 by the kidney (11, 36), and outer medullary osmolality is augmented. Therefore, we next investigated whether hyperosmolality enhances ET-1 release by the THAL by measuring the effect of osmolality on ET-1 release in primary cultures of THALs. Raising osmolality from 300 to 400 mosmol/kgH2O using NaCl increased ET-1 release from 62 ± 7 to 113 ± 2 pg﹞mg protein–1﹞h–1 (P
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We recently reported that ET-1 increases THAL eNOS expression via activation of ETB receptors (10). To determine whether ET-1 acting via ETB receptors mediates the effects of hyperosmolality in vitro, we investigated the effect of a selective ETB receptor antagonist, BQ-788, on hyperosmolality-induced increases in eNOS expression. In primary cultures of mTHALs, adding 1 μM BQ-788 to the culture medium 60 min before the hyperosmotic medium (400 mosmol/kgH2O, produced by adding NaCl) significantly blocked the increase in eNOS expression caused by hyperosmolality (70 ± 13% vs. –5 ± 10%; P

DISCUSSION. _( y, \& N  u: N$ v) K6 M
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A high-salt diet increases eNOS expression in the outer medulla in general and the THAL in particular. Increased eNOS expression in the renal medulla of animals fed a high-salt diet was first reported by Mattson and Higgins (21). We found that part of the increase in medullary eNOS was due to increased expression in the THAL (24). Because eNOS-derived NO inhibits net sodium flux in the THAL (31), the increased eNOS expression induced by high salt may be important during chronic adaptation to a high-salt diet. However, the mechanisms by which high salt stimulates eNOS expression are unclear. To address this issue, we studied the role of changes in medullary osmolality and ET in the salt-induced increase in THAL eNOS expression.

ET production by the kidney is enhanced by a high-salt diet (11, 36), and the THAL produces ET-1 (14). We also reported that ET-1 increases eNOS expression in vitro via activation of THAL ETB receptors (10). Consequently, we investigated whether this peptide is involved in high-salt stimulation of eNOS expression in the THAL. First, we examined the effects of high salt on THAL eNOS expression. As we reported previously (24), we found that 7 days of a high-salt diet increased THAL eNOS expression by 125%. We found no differences between groups with regard to total DNA or DNA/protein ratios between groups, indicating that the effects of the high-salt diet on eNOS expression were not due to hyperplasia or hypertrophy. To study whether ET-1 is involved in this stimulation, we tested the ability of bosentan, a dual-ETA/ATB receptor antagonist, to block the increase in eNOS expression caused by high salt. We found that blockade of ET receptors in vivo significantly reduced the stimulation of eNOS expression caused by high salt. These data indicate that ET is involved in the signaling pathway that stimulates eNOS.
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Previous observations have shown that selective ETB receptor antagonism in vivo leads to hypertension when animals are placed on a high-salt diet (33). To make sure bosentan did not increase blood pressure, we measured systolic blood pressure in conscious rats treated with either vehicle or bosentan. We found that the dual-ET receptor antagonist at 100 mg﹞kg–1﹞day–1 did not increase mean arterial pressure when rats were on high salt. To be sure bosentan did not alter tissue osmolality, we also measured outer medullary osmolality in both groups but found no significant differences between them. Thus the effects of bosentan were not due to changes in either blood pressure or tissue osmolality. However, bosentan may alter distribution of blood flow or other parameters (not measured) that may affect eNOS expression in the THAL, and therefore the effects of bosentan on eNOS expression may be due to blockade of other ET receptors besides those on the THAL.4 B- {7 H2 W5 t0 W

The tonicity of the renal medulla varies according to diet and water consumption, and changes in tonicity alter expression of many proteins (4). To study whether changes in medullary tonicity mediate the effects of high salt on eNOS expression, we first measured the osmolality of the cortex and outer medulla of rats on high salt. We found that high salt produced a 60-mosmol/kgH2O increase in outer medullary osmolality. Thus this increase in osmolality could stimulate ET release and enhance eNOS expression.% k7 ^3 q- J' ~% b" s! p

To test whether an increase in osmolality per se stimulates eNOS expression, we challenged primary cultures of THALs with hypertonic solutions and measured eNOS expression. Because 7 days of a high-salt diet increased outer medullary osmolality from 362 to 423 mosmol/kgH2O in vivo, we used similar increases. We found that increasing osmolality by 50 and 100 mosmol/kgH2O using NaCl increased eNOS expression by 39 and 71%, respectively. These in vitro data match the in vivo results remarkably well. Similar results were found when we raised medium osmolality by adding mannitol or urea. Taken together, these data suggest that hyperosmolality per se stimulates eNOS expression independently of solutes.
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Increases in renal medullary osmolality have been reported in other models such as water deprivation (2, 20). Shin et al. (38) showed that eNOS mRNA in the renal medulla of water-deprived rats increased threefold, suggesting that osmolality may play a role in its regulation. High interstitial osmolality alters activity of the solute transporters and enzymes involved in solute accumulation and in expression of the genes encoding the enzymes required for solute synthesis (29).9 o% F4 c0 I4 m. R
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Unlike NaCl or mannitol, urea is considered a nonactive osmolyte because it is generally membrane permeant and therefore does not alter cell volume. However, we considered it important to investigate its effect because it is one of the main components of the renal medullary interstitium and has been reported to contribute to the increased medullary osmolality observed in water deprivation (7, 9). We found that just like NaCl and mannitol, hyperosmolality induced by urea stimulated THAL eNOS expression. This may be due to the fact that the THAL has low urea permeability (13). Thus urea may alter cell volume in this segment, unlike other segments. In this regard, Grunewald et al. (8) reported that rabbit THALs exposed to urea-induced hyperosmolality shrank to 72% of isosmotic volume. Thus urea appears to be an active osmolyte in the THAL, acting in a manner similar to NaCl. However, urea has been shown to activate extracellular signal-regulated kinase (5), which raises the possibility that in addition to acting as an osmolyte it also activates signaling cascades independently of tonicity.- ?8 i+ o5 B% ?
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Our in vivo data indicate that ET is involved in salt-induced increases in eNOS expression. The involvement of ET-1 in mediating THAL eNOS expression during high salt intake may occur through several mechanisms such as upregulation of ETB receptors as well as increased ET-1 content or release. To investigate whether osmolality per se can stimulate ET release, we measured ET-1 in the medium of primary THAL cultures before and after exposure to increased osmolality and found that this increase enhanced ET-1 release by 82%. When animals are fed a high-salt diet, urinary ET-1 increases, suggesting that renal ET-1 production is augmented (36). However, it is not known which renal cells are responsible for such an increase. Our data indicate that ET release from the THAL may account for part of this effect. Our finding that hyperosmolality stimulates ET-1 release by the THAL correlates with studies showing that hyperosmolality induced by NaCl increased ET-1 release and mRNA in the rabbit inner medullary collecting duct (43) and ET-1 synthesis in cultured Madin-Darby canine kidney cells (17). In contrast, the ET content of the outer medulla reportedly does not change when animals are placed on high salt (36). On the other hand, Kohan and Padilla (15) revealed an inhibitory effect of hyperosmolality on urinary ET-1 and ET-1 mRNA in the rat inner medullary collecting duct. The reason for this discrepancy is unclear./ c9 G( E- p8 m& Z8 z

To investigate which ET receptor is responsible for the increase in eNOS caused by hyperosmolality, we tested the ability of an ETB receptor antagonist to block this effect. We found that an ETB antagonist blocked the ability of osmolality to stimulate eNOS expression. We previously showed that ET-1 stimulates eNOS expression in the THAL via activation of ETB receptors and that ETA receptors play no role in this process (10). Therefore, we concluded that a high-salt diet increases outer medullary osmolality. This increase in tonicity enhances ET release by the THAL, and ET acting via the ETB receptor increases eNOS expression in this segment.

Our finding that ET-1 stimulates eNOS expression via activation of ETB receptors correlates with other studies showing the same effect of ET-1 in other types of cells. For instance, Zhang et al. (45) found that ET-1 increased eNOS protein expression in bovine pulmonary artery endothelial cells, while Ye et al. (44) reported that ET-1 increased eNOS expression in cultured epithelial cells from the inner medullary collecting duct./ M  e3 c  }5 m+ E6 P! n! ]
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Previous reports from our laboratory demonstrated that although high salt intake for 7 days augments THAL eNOS expression, it does not lead to enhanced NO production (22). Thus one may question the physiological significance of the increase in eNOS expression. The increased expression may be required to offset counterregulatory mechanisms that inhibit NOS activity. The arginine analog asymmetrical dimethylarginine, a competitive NOS inhibitor, is increased when high salt intake is elevated (37). Thus the increase in expression may be a mechanism to prevent NO levels from falling. Alternatively, we previously showed that although NO production does not increase after 7 days on high salt, the effect of a given amount of NO does increase (22). These data indicate that the signaling cascade activated by NO is sensitized. We are currently testing the hypothesis that the effect of high salt on eNOS activity is biphasic. Initially, high salt stimulates eNOS expression and NO production; however, as NO levels increase, sensitivity of the cGMP signaling cascade also increases. Then, eNOS activity and NO production return to basal levels due to autoinhibition of eNOS by NO. Various investigators reported the existence of such a short-loop feedback (in which NO inhibits NOS activity) in other kinds of cells (3, 41), and we are currently investigating whether this also occurs in the THAL. This mechanism requires an initial increase in NO production that is caused by heightened eNOS expression.
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We do not think it is likely that increased superoxide levels are scavenging NO, because we found that THAL superoxide levels are decreased in animals fed a high-salt diet (40). In the THAL, NAD(P)H oxidase is probably a major source of O2–. NAD(P)H oxidase expression is likely to be reduced when rats are on high salt due to reduced ANG II levels (28). However, catabolism of O2– may also be involved. In Dahl salt-resistant rats, a high-salt diet increases medullary manganese superoxide dismutase expression, which catabolizes O2–, and total medullary O2– production is not increased (22).6 f3 G  `5 S3 Q# E2 F* [6 w
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The mechanism we describe here may be important in regulation of Na reabsorption by the THAL and Na excretion by the kidney when dietary salt intake is increased. Clarifying the physiological regulatory mechanisms of salt excretion by the kidney during high salt intake is important for understanding the pathophysiology of salt-sensitive hypertension, a disease that affects a large percentage of the population.

GRANTS5 `, L1 F: C. v  |, j# c) k2 @9 Q
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This work was supported by National Institutes of Health Grants HL-28982 and HL-70985 to J. Garvin.9 X9 |* F/ H7 {& w- |1 t, c/ M
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FOOTNOTES4 D1 _2 }$ [/ x; e
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.2 I& z* z/ Q4 Q6 c" F. e

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