Vol. 278, Issue 5, H1565-H1570, May 2000
Vagus nerve is involved in lack of blood reflow into sinusoids
after rat hepatic ischemia
Toshirou
Nishida1,
Shigeyuki
Ueshima1,
Hiromu
Kazuo1,
Toshinori
Ito1,
Akitoshi
Seiyama2, and
Hikaru
Matsuda1
Departments of 1 Surgery and
2 Physiology, Osaka University Medical
School, Suita, Osaka 565-0871, Japan
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ABSTRACT |
Although recovery of microcirculation is an important
determinant for ischemia-reperfusion injury, little information
is available about hepatic blood flow after ischemia. To
examine regulatory mechanisms of postischemic hepatic microcirculation,
we studied the sinusoidal blood flow after portal triad clamping of rat
livers for 5, 15, or 30 min. Hepatic tissue blood flow and erythrocyte blood flow in sinusoids were measured using a laser-Doppler flowmeter and an intravital microspectroscope, respectively. There was a time of
no blood flow (lag time) in sinusoids after declamping, dependent on
the ischemic time. Cholinergic blockade agents eliminated the lag time,
whereas nerve stimulation at the hiatus esophagus or on the
hepatoduodenal ligament during reperfusion prolonged it. Chemical
denervation with 10% phenol or surgical denervation on the
hepatoduodenal ligament eliminated the lag time. The prolongation of
lag time by nerve stimulation was completely abrogated by truncal vagotomy. These results suggest that the cholinergic vagus nerve is
involved in causing the lag time of sinusoidal blood flow in hepatic
ischemia-reperfusion.
ischemia-reperfusion; blood flow; portal triad clamping; hepatic microcirculation
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INTRODUCTION |
THE LIVER RECEIVES a total blood flow of 1.0-1.3
ml · min
1 · g1,
nearly 25% of the cardiac output, from the portal vein and hepatic artery. The blood flow from the hepatic artery contributes one-fifth to
one-fourth of the total hepatic blood flow, although differences exist
among animal species. The hepatic blood flow is regulated not only by
humoral factors but also by the nervous system (8, 9, 17).
-Agonists, endothelins acting through the B receptors, and nitric
oxide (NO) dilate hepatic vasculature, decrease resistance, and
increase hepatic blood flow, whereas 
-agonists, vasopressin, and
endothelins acting through the A receptor constrict the vasculature, increase resistance, and decrease blood flow (8, 18, 20, 22, 28).
Temporary portal triad clamping (PTC) is commonly used in liver surgery
to reduce intraoperative blood loss (4, 24), and hepatic
ischemia is inevitable in liver transplantation.
Ischemia and subsequent reperfusion lead to damage to cells and
organs depending on the ischemic time and restoration of tissue blood flow, and correlation between microscopic tissue perfusion and the
degree of ischemia-reperfusion injury has been described (27). No reflow or decreased blood flow after reperfusion may exacerbate the
cellular and organ damage after ischemia-reperfusion. However, the regulatory mechanisms of hepatic blood flow under both
physiological and pathological conditions are poorly understood, and
there is little information about the recovery of hepatic
microcirculation after temporary ischemia (5, 17). In the
present study, we studied in detail the recovery of postischemic
sinusoidal blood flow using a laser-Doppler flowmeter, a dual-spot
microspectroscope, and an ultrasonic transit-time volume flowmeter. The
results showed that there is a time of no blood flow in sinusoids after
reperfusion of the hepatic artery and portal vein and that the time of
no blood flow is regulated by the parasympathetic nerve, the vagus nerve.
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MATERIALS AND METHODS |
Reagents.
E5880, a platelet-activating factor antagonist, was a gift from Eizai
(Tokyo, Japan). Vinblastine and allopurinol were purchased from Sigma
Chemical (St. Louis, MO). All other chemicals were of analytic grade.
Animals and procedures.
Male Lewis rats weighing 200-250 g were deprived of food and had
free access to water for 12 h prior to the experiments. All animal
experiments were conducted in accordance with our institutional guidelines for the care and use of laboratory animals. Rats were anesthetized with pentobarbital sodium (40 mg/kg body wt ip) and allowed to breathe spontaneously. Catheters were inserted into the
femoral artery and a tributary of the superior mesenteric vein for
monitoring the systemic arterial and portal venous pressures, respectively. Physiological saline (1.5 ml · h1 · kg
body wt1) was infused with an infusion pump (model 11, Harvard Apparatus, South Natick, MA) from a catheter inserted in the
femoral vein throughout the experiments.
PTC was performed for 5, 15, or 30 min by gently placing a
microvascular clip on the hepatoduodenal ligament, in which the hepatic
artery, portal vein, and bile duct are present (11). After transient
ischemia for the indicated times, the clip was released and
hepatic tissue blood flow was measured using a laser-Doppler flowmeter
or an intravital microspectroscope. In separate experiments, we
measured the postischemic hepatic blood flow after PTC using portal-systemic shunt rats as described by Meredith and Wade (18) to
rule out the effects of gastrointestinal congestion. Briefly, the
spleen was subcutaneously transpositioned with the splenic vasculature,
which is reported (18) to enable anastomosis to develop between the
splenic capsule and the abdominal wall. After 4 days, PTC was performed
to measure the postischemic hepatic blood flow and portal venous
pressure. Clamping of the hepatoduodenal ligament other than the bile
duct was performed as follows: the common bile duct was gently
isolated, and a microvascular clip was placed on the hepatoduodenal
ligament without clamping the bile duct. Nerve stimulation using an
electronic stimulator (SEN-3101, Nihon Kohden, Osaka, Japan) was
performed by placing a bipolar platinum electrode around either the
hepatoduodenal ligament or the hiatus esophagus with rectangular
monophasic pulses of 10-Hz frequency, 2-ms duration, and 40-V
amplitude, from 10 min before declamping until 20 min after declamping
(10, 12). In separate experiments, a catheter was inserted into the
vena cava through the jugular vein and blood samplings were made before
PTC (for 15 min) and 5 min after PTC. The plasma endothelin-1 level was measured by RIA as previously reported (22).
Measurement of hepatic microcirculation.
A laser-Doppler flowmeter (ALF 21, Advance, Tokyo, Japan) was used for
monitoring hepatic tissue blood flow. After a baseline recording of 10 min, we performed the ischemic procedures for the indicated times. The
postischemic hepatic blood flow was monitored for 30 min after release
of the microsurgical clip. Hepatic blood flow monitoring was conducted
in the same area of the left lateral lobe.
Measurements of blood flow of the hepatic artery and the portal vein in
the hepatoduodenal ligament were performed with an ultrasonic
transit-time volume flowmeter (USTF; T206, Transonic Systems, Ithaca,
NY) using a miniature flow probe, a 2SB-reflector probe. USTF was
placed on the hepatic side of the hepatoduodenal ligament to measure
the blood flow in the hepatoduodenal ligament. PTC was performed for 15 min by gently placing a microvascular clip on the intestinal side of
the hepatoduodenal ligament.
The apparatus and the analytic method for using the intravital
microspectroscope were essentially the same as those reported previously (14, 22, 26). Three units were combined with a microscope:
1) a computer-controlled scanning spectrophotometer for
measuring the visible spectra of tissues and erythrocytes to obtain the
O2 saturation (SO2) of Hb
flowing in single sinusoids, 2) two photomultipliers for
measuring the erythrocyte velocity (v) according to the
dual-spot cross-correlation method, and 3) a CCD camera and an
image analyzer for measuring the sinusoid diameter (D) and
length of the sinusoid. To examine the changes in Hb content and
oxygenation in the left lateral lobe, we guided transmitted light from
a 340-µm spot diameter to a microspectroscope through a 5-mm-diameter
optical fiber, instead of a 400-µm-diameter fiber, which enabled
measurement of the spectral change of the liver at a depth of 3-5
mm. The difference in absorption between 577 and 586 nm was used for
monitoring changes in blood oxygenation, where 577 nm is the -band
peak of oxygenated Hb and 588 nm is the isosbestic point of oxygenated
and deoxygenated Hb. The difference in absorption between 586 and 603 nm was used for monitoring changes in the Hb concentration, where 603 nm was used as the reference wavelength because of the small difference
in molar extinction coefficient between oxygenated and deoxygenated Hb.
Drugs and treatment.
Heparin (20 IU · kg body
wt1 · h1)
and trinitroglycerin (30 µg · kg body
wt1 · h1)
were infused intravenously from 30 min before the experiments until the
end of experiments. E5880 (13 mg/kg body wt), a platelet-activating factor (PAF) inhibitor, was injected intramuscularly 12 h and 1 h
before the experiments. Vinblastine (1.6 mg/kg body wt) dissolved in
distilled water was intraperitoneally administered to the rats 5 and 2 days before the experiments. The administration of vinblastine decreased the number of white blood cells from 6,800 ± 1,270 (mean ± SD, n = 5) to 1,780 ± 430 per cubic millimeter.
Allopurinol (50 mg/kg body wt), which reduces oxygen radical formation
by inhibiting xanthine oxidase, was administered intraperitoneally 1 h
before the experiments. Atropine (5 mg/kg), scopolamine (10 mg/kg), or
phenoxybenzamine (5 mg/kg) and propranolol (20 mg/kg) were administered
intraperitoneally 20 min before the experiments (10, 19). In the last
group, rats with hypotension shock were excluded from the study.
Guanethidine (100 mg/kg) was administered intraperitoneally 18 h before
the experiments (19). Chemical denervation was performed by applying
10% phenol on the hepatoduodenal ligament 20 min before the
experiments as described by Cucchiaro et al. (3). For surgical
denervation, the hepatoduodenal ligament was completely dissected and
skeletonized except for the hepatic artery, portal vein, and bile duct
(3). Truncal vagotomy was performed at the hiatus esophagus.
Statistical analysis.
The results are expressed as the means ± SD of five different
experiments (n = 5) unless otherwise indicated. The
data were analyzed with Student's t-test and one-way ANOVA
with the post hoc Scheffé's multiple comparison test. P
values <0.05 were considered significant.
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RESULTS |
Lack of blood flow in sinusoids after declamping.
Total clamping of the hepatoduodenal ligament stopped hepatic tissue
blood flow and the mean arterial blood pressure decreased from 100 ± 8 (mean ± SD; n = 5) to 60 ± 10 (n = 5) mmHg,
whereas the portal venous pressure was increased from 8 (mean of five different experiments) to 45 mmHg. After we released the microsurgical clip, the systemic blood pressure was restored to the preclamping level
(Fig. 1). The recovery of the systemic
blood pressure appeared to be faster than that of hepatic tissue blood
flow. There was a transient time of no hepatic tissue blood flow (lag
time) after the microvascular clip was declamped (Fig. 1). The length
of the lag time appeared to depend on the time of ischemia
(Table 1). The portal venous pressure and
blood flow in the hepatoduodenal ligament were measured (Fig.
2). After declamping, the portal venous
pressure returned to the preclamping level within a few seconds. Blood
flow in the hepatoduodenal ligament, which mainly consisted of portal
blood flow (11), showed an initial transient blood flow and then
rapidly decreased to the basal line, which was followed by a gradual
increase in the blood flow. PTC decreased the liver thickness, and
declamping engorged the liver and increased the liver thickness. After
hepatic tissue blood flow was initiated, the liver size and thickness
were gradually normalized. The blood levels of endothelin-1 before and
after PTC were 1.6 ± 0.8 (n = 6) and 2.2 ± 1.4 (n = 6) pg/ml, respectively, and there was no significant difference between
their values (P = 0.1664).
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Fig. 1.
Recovery of hepatic tissue blood flow after temporary portal triad
clamping (PTC). In rats under pentobarbital sodium anesthesia (40 mg/kg), the portal vein and hepatic artery were occluded for 5, 15, or
30 min, followed by reperfusion with declamping of microsurgical clip.
Top: changes in hepatic tissue blood flow measured by
laser-Doppler flowmetry; bottom: changes in systemic blood
pressure. Data from 5 similar experiments are represented by a typical
trace. Typical traces measured by laser-Doppler flowmeter are shown
(top).
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Table 1.
Lag time after transient portal triad clamping measured by
laser-Doppler flowmeter or by in vivo microspectroscope
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Fig. 2.
Changes in afferent vessel blood flow and blood pressure after
temporary PTC. In rats under pentobarbital sodium anesthesia (40 mg/kg), the portal vein and hepatic artery were occluded for 15 min,
followed by reperfusion with declamping of microsurgical clip. Blood
flow in the hepatoduodenal ligament measured by ultrasonic transit-time
volume flowmeter (USTF; top) and portal venous pressure
(bottom) were monitored before, during, and after PTC. Typical
traces measured by USTF are shown (top).
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Because laser-Doppler flowmetry is sensitive to blood flow changes in
the hepatic artery and to blood flow changes after venous stasis in
areas near the liver surface (1, 2), we directly measured sinusoidal
blood flow (erythrocyte velocity) using a microspectroscope (Fig.
3). After PTC, the microspectroscope
demonstrated collapse of sinusoids within several minutes and a lack of
erythrocytes flowing in sinusoids. There were erythrocytes in the
central veins, terminal portal veins, and other large vessels, where
the blood showed a to-and-fro movement. Erythrocytes flowed back into
collapsed sinusoids 2-7 min after declamping as observed by the
laser-Doppler flowmeter (Fig. 1 and Table 1). To confirm that these
changes in sinusoidal blood flow occurred not only in superficial
sinusoids but also in more deeply located sinusoids, we evaluated
changes in hepatic Hb content and oxygenation of the liver at 3- to
5-mm thicknesses using transmitted light and an intravital
microspectroscope. Data were not shown, but increases in hepatic Hb
content and oxygenation were initiated 1 min after declamping. The
results were consistent with the presence of lag time as observed by
the laser-Doppler flowmetry in principle (Fig. 1), but deeply located
sinusoids appeared to have faster recovery of blood flow than
superficially located sinusoids (Table 1). In the present study, the
lag time was defined as the time during which there was no erythrocyte flow in sinusoids between declamping and the reflow of erythrocytes. The lag time appeared to depend on the time of ischemia (Table 1).
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Fig. 3.
Recovery of sinusoidal erythrocyte flow after temporary PTC. The portal
vein and hepatic artery in the hepatoduodenal ligament were occluded
for 5, 15, or 30 min, followed by reperfusion with declamping of
microsurgical clip. Data from 5 similar experiments are represented by
typical traces measured by in vivo microspectroscope.  , 5-min
ischemia;  , 15-min ischemia;  , 30-min
ischemia.
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Effects of drugs and nerves.
To elucidate the mechanism of lag time formation, we examined the
effects of several humoral and nervous factors on sinusoidal blood
flow. Although the portal-systemic shunt operation inhibited the
increase in the portal pressure during PTC (mean portal pressure = 11 mmHg; n = 5), the lag time was not significantly affected (Table 2). Furthermore, partial clamping of
the left lateral lobe also avoided portal congestion and caused a
similar lag time (mean = 2.1 min, n = 2). Extrahepatic bile
duct obstruction was reported (19) to be associated with decreased
portal blood flow. However, the lag time was not eliminated by clamping
the hepatoduodenal ligament other than the choledocus (Table 2). An
anticoagulant (heparin), a PAF inhibitor (E5880), and an NO donor
(trinitroglycerol) were ineffective in eliminating the lag time.
Allopurinol and vinblastine also failed to eliminate the lag time.
Pretreatment with cholinergic blockade agents, such as atropine and
scopolamine, however, did eliminate the lag time, although a ganglion
blocker (guanithidine) and - and -adrenergic blocking agents did
not. These results suggested possible involvement of the cholinergic nerve in causing the lag time.
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Table 2.
Effects of various agents and procedures on lag time after 15-min
portal triad clamping (measured by laser Doppler flowmeter)
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Next, we examined the involvement of the sympathetic and
parasympathetic nervous systems. Surgical denervation and treatment with phenol (chemical denervation) on the hepatoduodenal ligament eliminated the lag time (Fig. 4 and Table
2). Stimulation of both intact sympathetic and parasympathetic nerves
on the hepatoduodenal ligament reduced the hepatic tissue blood flow to
70% under physiological conditions when measured by a laser-Doppler
flowmeter (data not shown). Nerve stimulation on the hepatoduodenal
ligament during reperfusion prolonged the lag time, and, after 6 min,
hepatic tissue blood flow showed a steep recovery and then rapidly
decreased to the final flow (Fig. 4). Vagus nerve stimulation at the
hiatus esophagus during reperfusion caused a similar prolongation of the lag time, whereas nerve stimulation at the celiac truncus had no
effect on either hepatic tissue blood flow or lag time (Table 2).
Stimulation of the distal vagus nerve combined with proximal truncal
vagotomy showed no lag time (Table 2). Similar results were obtained
using the microspectroscope (Table 1). These results suggested that the
vagus nerve is involved in causing the lag time.
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Fig. 4.
Effects of denervation and nerve stimulation. The portal vein and
hepatic artery were occluded for 15 min, followed by reperfusion with
declamping of microsurgical clip. Treatment methods for denervation and
nerve stimulation are described in MATERIALS AND METHODS.
Data from 5 similar experiments are represented by typical traces
measured by laser-Doppler flowmeter. Denervation eliminated lag time,
and nerve stimulation prolonged it.
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DISCUSSION |
The liver receives 67-80% of its blood flow from the portal vein
and 20-33% from the hepatic artery. Extrahepatic vascular pressures are 80-120 mmHg in the hepatic artery and 7-10 mmHg in the portal vein. Intrinsic regulation of hepatic arterial flow appears to be in the terminal arteriole and is reported (15) to be
regulated by the hepatic arterial buffer response. In contrast, portal
blood flow is not considered to be regulated by local mechanisms but
rather by the amount of blood received from the splanchnic circulation
(15, 17). We showed that the major initial blood flow after PTC comes
from the portal vein (11). In the present study, recovery of hepatic
blood flow after transient ischemia was evaluated. By PTC, the
systemic blood pressure showed a sudden and then a gradual decrease,
and its recovery after declamping appeared to be faster than that of
hepatic blood flow (Fig. 1). A sudden decrease in the systemic blood
pressure was observed in portal-systemic shunt rats (data not shown).
These data suggest that portal congestion may not be the main cause of
a decrease in systemic blood pressure during PTC. In contrast, the
portal venous pressure was increased by PTC and then gradually
decreased during PTC. After declamping, the portal venous pressure
rapidly decreased with transient blood flow in the hepatoduodenal
ligament, but there was no detectable hepatic tissue blood flow in
liver surface (Fig. 2). The portal blood pressure rapidly decreased with initial blood flow in the hepatoduodenal ligament measured by USTF
and with transient hepatic congestion. Although we have no direct
evidence, initial transient blood flow in the hepatoduodenal ligament,
hepatic congestion, and a rapid decrease in portal blood pressure after
declamping may suggest that deeply located sinusoids have blood flow
after declamping whereas superficially located sinusoids have no flow
(lag time), and thus there may be heterogeneity of sinusoidal blood
flow after PTC.
Sinusoidal erythrocyte flow is irregular or intermittent and sometimes
shows reversed flow even under physiological conditions (16). Clamping
the hepatic artery and portal vein on the hepatoduodenal ligament
caused interruption of sinusoidal erythrocyte flow and the collapse of
sinusoids within several minutes. By declamping, sinusoids were
refilled with flowing erythrocytes after a substantial lag time.
Although vasoconstriction may occur in the presence of oxygen radicals
(21), data from the study indicated that leukocytes themselves and
radicals derived from leukocytes or xanthine oxidase may not be
causative (Table 2). An increase in endothelin levels might be
causative (22, 28), but we could not detect any increase in the blood
levels of endothelin-1 in contrast to an endotoxin model (22). It is
reported (23) that acute biliary obstruction causes hemodynamic changes
in the liver. The results indicated that acute biliary obstruction does
not affect the presence of the lag time (Table 2). Furthermore, portal congestion during PTC is not considered to be involved in lag time
formation because portal-systemic shunt operation and partial clamping
of the left lateral lobe could not eliminate it.
Hepatic blood flow and vascular resistance respond to both neural and
humoral factors. Stimulation of hepatic sympathetic fibers derived from
the splanchnic nerves is reported to constrict the hepatic vasculature
via an 2-adrenergic mechanism, which results in
reduction of hepatic blood flow and hepatic blood volume, whereas
stimulation of the parasympathetic fibers, the vagus nerve, is reported
to open previously closed sinusoids (7). Stimulation of the hepatic
branch of the vagus nerve or the topical application of cholinergic
agonists, however, constricts portal venules and central veins, which results in a drastic decrease in
sinusoidal blood flow (13, 25). Noradrenagic nerve terminals were
reported (6) to be present in the periphery of cholinergic neurons and to cause vasoconstriction. Thus nervous regulation of the hepatic vascular response is complex and still controvesial. Our data showed
that an irreversible 1- and 2-adrenergic
antagonist (phenoxybenzamine) failed to eliminate the lag time and that
cholinergic blocking agents and procedures of cholinergic nerve block
eliminated the lag time (Table 2). Thus a cholinergic mechanism, rather
than an adrenergic mechanism, may be responsible for the lag time. However, it is still difficult to interpret the mechanism by which proximal truncal vagotomy eliminated the prolonged lag time induced by
distal nerve stimulation (Table 2), because in these experimental conditions the nerve stimulation is considered to have similar effects
on hepatic blood flow even after the proximal nerve was cut
(10). Afferent nerves may be partly involved in this
process; however, this could not solely account for the phenomenon
because efferent nerves to the liver were proximally cut and distally stimulated. Afferent nerves plus other mechanisms may be involved.
The presence of a lag time after transient ischemia has not
been reported in other organs, probably because of the lack of detailed
investigations of ischemic tissue microcirculation. It is unknown
whether there is a lag time after a short time of ischemia, i.e., 5-min ischemia, because the two methods used in this
study needed 10-15 s for stable measurements. In this connection,
it is interesting that complete collapse of sinusoids required several minutes. The reasons why the lag time was dependent on ischemic time
are not elucidated in the present investigation. Species differences
may be another important issue in this kind of study. For example,
blood flow patterns and their nervous regulation are different among
rats, dogs, cats, and humans. One other issue is that the use of
anesthetics, e.g., the pentobarbital sodium in the present study, may
affect the vascular response and blood flow after ischemia.
However, in clinical settings, ischemia-reperfusion of the
liver usually occurs under anesthesia. The clinical significance of the
lag time after transient ischemia has not been sufficiently addressed; however, the present findings indicate that even after the
clamps are removed, there still exists a part of the liver with no
blood flow, where hepatic tissue hypoxia continues.
In summary, there was an ischemic time-dependent period of no blood
flow in hepatic sinusoids after PTC. The cholinergic vagus nerve seemed
to be involved in causing the lag time.
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ACKNOWLEDGEMENTS |
This work was supported in part by Grants-in-Aid for Scientific
Research from the Ministry of Education, Science, and Culture of Japan.
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FOOTNOTES |
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T. Nishida, Div.
of General and Gastroenterological Surgery, Dept. of Surgery, E1, Osaka
Univ. Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka
565-0871, Japan (E-mail: toshin{at}surg1.med.osaka-u.ac.jp).
Received 15 September 1999; accepted in final form 16 November
1999.
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