Vol. 275, Issue 2, R541-R547, August 1998
Cholinesterase affects dynamic transduction properties from
vagal stimulation to heart rate
Tsutomu
Nakahara,
Toru
Kawada,
Masaru
Sugimachi,
Hiroshi
Miyano,
Takayuki
Sato,
Toshiaki
Shishido,
Ryoichi
Yoshimura,
Hiroshi
Miyashita, and
Kenji
Sunagawa
Department of Cardiovascular Dynamics, The National
Cardiovascular Center Research Institute, Suita, Osaka, Japan
 |
ABSTRACT |
Recent investigations in our laboratory
using a Gaussian white noise technique showed that the transfer
function representing the dynamic properties of transduction from vagus
nerve activity to heart rate had characteristics of a first-order
low-pass filter. However, the physiological determinants of those
characteristics remain to be elucidated. In this study, we stimulated
the vagus nerve according to a Gaussian white noise pattern to estimate the transfer function from vagal stimulation to the heart rate response
in anesthetized rabbits and examined how changes in acetylcholine kinetics affected the transfer function. We found that although increases in the mean frequency of vagal stimulation from 5 to 10 Hz
did not change the characteristics of the transfer function, administration of neostigmine (30 µg · kg
1 · h1
iv), a cholinesterase inhibitor, increased the dynamic gain from 8.19 ± 3.66 to 11.7 ± 4.88 beats · min1 · Hz1
(P < 0.05), decreased the corner
frequency from 0.12 ± 0.05 to 0.04 ± 0.01 Hz
(P < 0.01), and increased the lag
time from 0.17 ± 0.12 to 0.27 ± 0.08 s
(P < 0.05). These results suggest
that the rate of acetylcholine degradation at the neuroeffector
junction, rather than the amount of available acetylcholine, plays a
key role in determining the dynamic properties of transduction from vagus nerve activity to heart rate.
systems analysis; Gaussian white noise; dynamic stimulation; rabbit
| |
INTRODUCTION |
ALTHOUGH THERE IS AN ABUNDANCE of literature regarding
the vagal control of heart rate (HR), the determinants of the dynamic properties of transduction from vagus nerve activity to HR remain to be
elucidated. Previous investigations using dynamic systems analysis have
shown that HR minimally responds to changes in vagus nerve activity in
the high-frequency range (>0.1 Hz); that is to say, the transfer
function from vagal stimulation to HR response has low-pass filter
characteristics (2, 6, 18, 19, 22, 26). Inasmuch as the characteristics
of the transfer function represent the dynamic transduction properties
relating vagus nerve activity to HR, a detailed analysis of the
transfer function would likely enable an identification of the
physiological determinants of these dynamic transduction properties.
Stimulation of the vagus nerve causes a cascade reaction involving the
release of acetylcholine (ACh), which in turn leads to changes in the
membrane ionic currents of the pacemaker cell (15). Characteristics of
the rate-limiting step in the signaling pathway might be the main
determinants of the dynamic transduction properties relating vagus
nerve activity to HR. In studies on the rabbit sinoatrial node, it was
shown that the diffusion of ACh markedly affected the time course of
the muscarinic response (i.e., hyperpolarization) (23, 24).
Furthermore, other observations (5, 13, 35) and mathematical models of
underlying cellular mechanisms responsible for the changes in HR
elicited by vagal stimulation predict that ACh concentration in
neuroeffector junctions of the sinus node responds more slowly
to changes in vagus nerve activity than does the membrane ionic
currents to changes in ACh concentration (9-12, 22). Thus we
hypothesized that the changes in ACh kinetics might critically
affect the dynamic properties of transduction from vagus nerve activity
to HR.
To examine this hypothesis, we modulated both the mean frequency of
vagal stimulation and cholinesterase (ChE) activity, and evaluated the
resulting changes in the transfer function from vagal stimulation
frequency to HR response in anesthetized rabbits. The results suggested
that ChE activity plays an important role in determining the dynamic
properties of transduction from vagus nerve activity to HR.
| |
MATERIALS AND METHODS |
Surgical preparations.
Animal care was in accordance with institutional guidelines. Fourteen
Japanese White rabbits weighing 2.4-3.0 kg were anesthetized using
urethan (250 mg/kg iv) and 
-chloralose (40 mg/kg iv) and mechanically ventilated with oxygen-enriched room air. Supplemental doses of anesthetics were given via the right femoral vein as necessary. Aortic pressure was monitored by means of a micromanometer catheter (model PC-340, 3F, Millar Instrument, Houston, TX) inserted via the left femoral artery. A catheter was inserted into the right
femoral vein for the administration of drugs. The bilateral carotid
sinus nerves and aortic depressor nerves were cut to eliminate the
effects of the arterial baroreflex systems. We transected the bilateral
sympathetic nerves at the level of the stellate ganglion to eliminate
the possible interaction between the vagus and sympathetic nerves.
Vagus nerves were sectioned bilaterally at the neck, where a pair of
bipolar platinum electrodes was attached to the cardiac end of the
sectioned right vagus nerve for stimulation. To prevent drying and to
provide insulation, the stimulation electrodes and the nerve were
immersed in a mixture of white petrolatum (Vaseline) and paraffin.
Finally, a pair of bipolar stainless steel electrodes was sutured to
the right atrium to record the cardiac electrogram for monitoring of
HR. During all experiments, body temperature was maintained at 37°C
with a heating pad.
Experimental procedures.
The pulse duration of nerve stimulation was set at 2 ms. We adjusted
the amplitude of vagal stimulation to yield an HR decrease of ~50
beats/ min at 5 Hz. This resulted in an amplitude ranging from 2.5 to
4.0 V (3.0 ± 0.9 V). To estimate the dynamic transduction properties, we stimulated the vagus nerve using a pulse train that was
frequency modulated by a band-limited Gaussian white noise (2, 18, 19,
31). The instantaneous stimulation frequency was switched one time per
second, yielding an input power spectrum that was fairly constant up to
0.5 Hz, decreased gradually to 1/10 at ~0.8 Hz, and attenuated
sharply as the frequency increased to 1 Hz. We estimated the transfer
function only up to 0.8 Hz, because the lack of input power
above that frequency made estimation unreliable. The frequency
range was nevertheless sufficient in spanning the physiological
frequency range of vagal HR regulation (2, 18, 19).
In the first series of experiments (n = 6), we examined how changes in the mean frequency of the
Gaussian white noise input vagal stimulation pattern affected the
transfer function from vagal stimulation frequency to HR response. We
set the mean stimulation frequency at either 5 or 10 Hz, with a
standard deviation of frequency modulation of 2 Hz. We used different
Gaussian white noise perturbation command sequences for
different animals while keeping the statistical characteristics of the
perturbation sequences, such as the mean frequency and
standard deviation, unchanged. We also randomized the order of
stimulation among the animals to reduce the likelihood of bias or
systematic errors in our identification approach. After steady-state
conditions were reached with each mean frequency change, we recorded
both the vagal stimulation frequency and HR for 10 min.
In the second series of experiments (n = 8), we examined how the inhibition of ChE influenced the transfer
function. After first recording the control HR response to dynamic
vagal stimulation with Gaussian white noise (5 ± 2 Hz), we repeated
the same protocol 15-20 min after initiation of continuous
intravenous infusion of neostigmine at 30 µg · kg1 · h1
(Sigma, St. Louis, MO). This was the maximum dose, identified in
preliminary experiments, beyond which hemodynamic instability ensued.
HR and vagal stimulation frequency were digitized at 200 Hz using a
12-bit analog-to-digital converter and stored on the hard disk of a
dedicated laboratory computer system (NEC PC-98, Tokyo, Japan). We calculated the mean level of HR before vagal stimulation by
averaging instantaneous HR for 10 s before the stimulation. The mean
level of HR during vagal stimulation was calculated by averaging
instantaneous HR over the time period (10 min).
Estimation of the transfer function.
After applying an antialiasing filter, we resampled the input (vagal
stimulation frequency)-output (HR) data pairs at 10 Hz and
then segmented the data into eight 50%-overlapping segments of 1,024 data points each. For each segment, the linear trend was
subtracted and a Hanning window was applied. We then performed a fast
Fourier transformation to obtain the frequency spectrum of nerve
stimulation frequency [N(f)] and of HR response
[HR(f)]. The frequency resolution was 0.01 Hz.
We ensemble averaged, over the eight segments, the power of the nerve
stimulation
[SN · N(f)],
the HR response
[SHR · HR(f)], and the cross power between them
[SN · HR(f)].
Finally, we obtained the transfer function relating nerve stimulation
frequency to HR response [H(f)] using the following
equation
|
(1)
|
The
modulus [|H(f)|] and phase shift
[
(f)] of the transfer function were derived from its
real part [HR(f)] and
imaginary part [HI(f)]
using the following equations
|
(2)
|
|
(3)
|
The
modulus indicates the relative amplitude of HR change per unit change
in nerve stimulation frequency and is expressed in units of beats per
minute per hertz. We hereafter refer to the modulus as the gain of the
transfer function. The phase shift is also a function of frequency and
indicates, with respect to the input, a lag or lead in the output
normalized by its corresponding frequency.
Because the transfer function from vagal stimulation frequency to HR
response approximated a first-order low-pass filter with lag time (18),
we parameterized the transfer function using the following
equation
|
(4)
|
where K is the estimated gain at zero frequency (and referred to
hereafter as dynamic gain), f is the frequency,
fc is the corner frequency at
which the gain decreases by 3 dB from its steady-state value, and L is
the lag time. L is defined as the time delay between the input and the
output of the system without any distortion of the input signal (20).
The negative sign in front of K in the equation results from the
negative HR response to vagal stimulation.
To quantify the linear dependence of the HR response to nerve
stimulation, we estimated the coherence function [Coh(f)]
using of the following equation
|
(5)
|
After estimating the transfer functions, we used inverse
Fourier transformation to determine the corresponding step response of
HR to a 1-Hz nerve stimulation step input to easily visualize the
system characteristics. The length of the calculated step response was
51.2 s. We derived the maximum step response by averaging the last 10 s
of the estimated step response. The 90% rise time of the step response
was also calculated relative to the maximum step response.
We calculated the time constant
(
) and the rate constant
(K) from
fc using the following equations
|
(6)
|
|
(7)
|
Statistical analysis.
We used Student's paired t-test for
the statistical analysis of paired data. Differences were considered
statistically significant if P < 0.05. All values are presented as means ± SD.
| |
RESULTS |
Effect of mean frequency on transfer function.
Figure 1 shows typical recordings of
vagal stimulation frequency as modulated by Gaussian white noise (Fig.
1, top) and associated HR responses
(Fig. 1, bottom). HR changed in a
fashion that was roughly reciprocal in relation to the stimulation
pattern. Dynamic vagal stimulation at 5 ± 2 and 10 ± 2 Hz
decreased the mean level of HR and mean aortic pressure relative to
prestimulation values (P < 0.05)
(Table 1). The mean level of HR during
stimulation at 10 ± 2 Hz was lower than that at 5 ± 2 Hz
(P < 0.01). In contrast, there was
no significant difference between mean aortic pressures in response to
vagal stimulations at 5 ± 2 and 10 ± 2 Hz.
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Fig. 1.
Representative recordings of vagal nerve stimulation (VNS) via
band-limited Gaussian white noise
(top) and associated heart rate (HR)
responses (bottom). Stimulation at
frequencies of 5 ± 2 Hz (A) and
10 ± 2 Hz (B) are shown.
|
|
Figure 2 shows the transfer function
obtained at stimulation frequencies of 5 ± 2 and 10 ± 2 Hz. The
gain plot (Fig. 2, top), phase plot
(Fig. 2, middle), and coherence
(Fig. 2, bottom) are shown.
Characteristics of the gain and phase plots match what is known as a
first-order low-pass filter with lag time. At the lowest frequencies,
the phase shift was nearly out of phase (i.e., -
radians) and
decreased further as frequency increased. The coherence was >0.8 in
the frequency range from 0.01 to 0.3 Hz, indicating strong linearity
between vagal stimulation and HR response in this frequency range. The
gains and phase shifts of the transfer functions and coherences
obtained at the two levels of stimulation frequency were not remarkably
different. Consequently, there were no significant differences between
the parameters characterizing the respective transfer functions, as
summarized in Table 2.
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Fig. 2.
Averaged transfer function from vagal stimulation frequency to HR
change obtained at stimulation frequencies of 5 ± 2 Hz
(A) and 10 ± 2 Hz
(B) (pooled data;
n = 6). Gain
(top), phase shift
(middle) and coherence function
(Coh, bottom) are shown. Note that
gain and frequency axes are logarithmically scaled. Solid lines, mean
values; broken lines, mean + SD values; bpm, beats/min.
|
|
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Table 2.
Effect of changes in mean frequency of vagal stimulation on parameters
of transfer function relating dynamic vagal stimulation to HR
|
|
The corner frequencies of HR response to vagal stimulation at 5 ± 2 and 10 ± 2 Hz were 0.10 ± 0.05 and 0.11 ± 0.04 Hz,
respectively (Table 2). This means that HR responded mainly to changes
in vagus nerve activity in frequencies <0.1 Hz. According to
Eqs. 6 and 7, defined in
MATERIALS AND METHODS, we calculated
the time constants from these corner frequencies and estimated the rate constants. There were no significant differences in the time constants (1.8 ± 0.7 vs. 1.7 ± 0.7 s) or the rate constants (0.66 ± 0.30 vs. 0.70 ± 0.28 s1) derived for the two
conditions of mean stimulation frequency.
Effect of neostigmine on transfer function.
Figure 3 shows typical recordings of vagal stimulation
frequency (Fig. 3, top) and
associated HR responses (Fig. 3,
bottom) before and during infusion
of neostigmine (30 µg · kg1 · h1
iv). Neostigmine decreased the mean level of HR both before and during
dynamic vagal stimulation (P < 0.01)
(Table 3). In contrast, although neostigmine showed a
tendency to decrease mean aortic pressure before vagal stimulation, the
change did not reach statistical significance. Neither were decreases
in mean aortic pressure elicited by vagal stimulation affected by
neostigmine.
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Fig. 3.
Representative recordings of VNS via band-limited Gaussian white noise
(top) and associated HR responses
(bottom) before (control,
A) and during infusion of
neostigmine (30 µg · kg1 · h1
iv, B).
|
|
Figure 4 shows the effect of neostigmine on the transfer
function from vagal stimulation frequency to HR response. The gain plot
(Fig. 4, top), phase plot (Fig. 4,
middle), and coherence (Fig. 4,
bottom) are shown. As summarized in
Table 4, neostigmine increased the dynamic gain from
8.19 ± 3.66 to 11.7 ± 4.88 beats · min1 · Hz1
(P < 0.05) and decreased the corner
frequency from 0.12 ± 0.05 to 0.04 ± 0.01 Hz
(P < 0.01). Neostigmine increased
the lag time from 0.17 ± 0.12 to 0.27 ± 0.08 s
(P < 0.05), suggesting a
prolongation of the latency of onset of the HR response to vagal
stimulation. However, neostigmine did not significantly affect the
coherence.
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Fig. 4.
Averaged transfer function from vagal stimulation frequency to HR
change before (A) and during
infusion of neostigmine (30 µg · kg1 · h1
iv, B) (pooled data,
n = 8). Gain
(top), phase shift
(middle), and Coh
(bottom) are shown. Solid lines,
mean values; broken lines, mean + SD values.
|
|
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Table 4.
Effect of neostigmine infusion (30 µg · kg1 · h1
iv) on parameters of transfer function relating dynamic vagal
stimulation to HR
|
|
Neostigmine significantly prolonged the time constants estimated from
the corner frequencies of the HR response to vagal stimulation from 1.5 ± 0.6 to 4.1 ± 0.9 s (P < 0.01). It also decreased the estimated rate constants from 0.75 ± 0.28 to 0.25 ± 0.05 s1
(P < 0.01). The rate constants were
in good agreement with those obtained from experimental and theoretical
studies (4, 5, 10-13, 17, 24).
Figure 5 shows the calculated step response of HR to a
1-Hz vagal stimulation step input before and during infusions of
neostigmine. Neostigmine increased the maximum step response of HR from
7.94 ± 3.98 to 11.4 ± 4.22 beats/min
(P < 0.05) and prolonged the 90% rise time from 4.40 ± 1.74 to 8.31 ± 4.15 s
(P < 0.01).
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Fig. 5.
Step response of HR calculated from transfer function obtained before
(control, A) and during infusion of
neostigmine (30 µg · kg1 · h1
iv, B). Neostigmine increased
maximum response and prolonged time period required for maximum
response. Solid lines, mean values; broken lines, mean  SD
values.
|
|
| |
DISCUSSION |
We showed that an increase in the mean frequency of vagal stimulation
did not change the transfer function from vagal stimulation frequency
to HR response, whereas neostigmine markedly affected it. These results
suggest that the dynamic properties of transduction from vagus nerve
activity to HR are affected by the rate of ACh degradation rather than
by the amount of available ACh.
It is well established that the muscarinic response to static vagal
stimulation depends on stimulation frequency and the activity of
acetylcholinesterase (1, 3, 25, 27, 28). In this study, we found that
decreases in the mean level of HR elicited by dynamic vagal stimulation
were dependent on mean stimulation frequency and potentiated by
neostigmine. In a previous report, a conceptual framework was proposed
wherein the operating HR is determined through a sigmoidal relationship
between autonomic nervous activity and HR (18). Although this framework
predicts that an increase in the mean frequency of vagal stimulation
decreases HR, thereby lowering the gain of the transfer function (2, 18), it is conceivable that, in this study, the shift of operating points caused by increases in the mean stimulation frequency from 5 to
10 Hz might not be large enough to noticeably change the gain. By
contrast, neostigmine increased the gain despite the fact that the mean
HR level during dynamic vagal stimulation at 5 ± 2 Hz with
neostigmine was similar to that during vagal stimulation at 10 ± 2 Hz without neostigmine (157 ± 16 vs. 157 ± 31 beats/min). Thus,
in the case of neostigmine, a shift in the HR operating point alone
cannot account for the observed alteration in the HR response to
dynamic vagal stimulation.
Neostigmine increased the gain and decreased the corner frequency of
the transfer function, reflecting an enhanced yet slowed HR response to
vagal stimulation in the time domain (Fig. 5). Because neostigmine not
only slows the degradation of ACh but also activates ACh receptors on
cardiac ganglion cells producing ACh release (1), the augmented HR
response might have resulted from an increase in the amount of ACh
released per vagal stimulus. Indeed, in this study, neostigmine evoked
slight (~10%) bradycardia with bilateral vagus nerve transection.
These results might be a manifestation of the neostigmine-induced
release of ACh from the cholinergic nerve terminals. However, if the
effects of neostigmine were ascribed solely to the increase in the
amount of ACh released per vagal stimulus, neostigmine should increase
the amplitude of the steady-state response to vagal stimulation without
affecting the 90% rise time of the response.
We evaluated the time required to reach steady state of the calculated
HR response to vagal stimulation in terms of the 90% rise time, lag
time included. Prolongation by neostigmine of the lag time, however,
was relatively quite small. The increase in rise time by neostigmine
therefore primarily reflects the slow dynamic nature of the step
response. In fact, neostigmine increased the time constants estimated
from the corner frequencies of the transfer function (1.5 ± 0.6 vs.
4.1 ± 0.9 s) and decreased the rate constants by ~70%
(0.75 ± 0.28 vs. 0.25 ± 0.05 s1). These values are in
good agreement with the previously estimated rate constants of ACh
degradation at the sinoatrial node (4, 5, 10-13, 17, 24). Although
the mechanism of increased lag time by neostigmine is unclear,
neostigmine seems to affect the HR response to vagal stimulation
primarily through inhibition of ACh degradation by ChE.
Intravenously administered neostigmine could affect the transmission
properties at the nerve ganglia as well as at the neuroeffector junction of the sinus node. We therefore cannot uniquely identify the
site of action of neostigmine. Cholinergic transmission in the
autonomic ganglia, however, is known to be as quick as that at the
neuromuscular junction of skeletal muscle (~1 ms) (4, 7, 14, 30).
Thus the delay associated with cholinergic transmission in the ganglia
is by far smaller than the time constants of the muscarinic
receptor-mediated cardiac response and of the HR response to vagal
stimulation in this study. Accordingly, it is conceivable that the
alteration by neostigmine of the transfer function from vagal
stimulation frequency to HR response might be mainly attributable to
the modulation of ACh degradation within the neuroeffector junction of
the sinus node.
In most cases, including this study, the low-pass filter
characteristics of the HR response were derived by modulating the vagal
stimulation frequency without taking into account the phase-dependent sensitivity of the sinus node to vagal inputs (16) (i.e.,
nonsynchronized vagal stimulation protocol). In contrast, Mokrane et
al. (22) found, using a synchronized vagal stimulation protocol, that
the transfer function was characterized by a combination of a low-pass filter with a corner frequency of 0.065 Hz and an all-pass filter. Their results suggest that at least two ACh-dependent components, a
slow component and a fast component, are involved in the vagal control
of HR. Furthermore, the authors predicted that the low-pass filter
characteristics of ACh concentration at the sinus node would affect the
filter characteristics of the HR response to vagal stimulation.
Inhibition of ChE would decrease the corner frequency of the low-pass
filter characteristics of ACh kinetics, thereby decreasing that of the
transfer function from vagal stimulation frequency to HR response. Thus
their theoretical prediction was in line with our experimental
observations. With regard to the corner frequency of the low-pass
filter characteristics of the HR response to nonsynchronized modes of
vagal stimulation, the values for the rabbit (0.12-0.15 Hz) (18,
26) and the dog (0.15 Hz) (2) are higher than those obtained from the
cat (0.05 Hz) (6). The present data are in good agreement with those obtained from previous rabbit experiments (18, 26). The differences in
corner frequencies among various animal species may be due to
differences in the concentration of acetylcholinesterase strongly influencing the rate of ACh degradation.
Clinically, ChE inhibitors, such as neostigmine, coupled with
anticholinergic drugs are used to reverse muscle relaxation at the end
of surgery (21, 29). In a mathematical modeling study, Dexter et al.
(12) demonstrated that the combination of a ChE inhibitor and an
anticholinergic drug decreased the amplitude of the high-frequency HR
variation corresponding to respiratory sinus arrhythmia. A more recent
study on humans supported this prediction (32). These results suggest
that the rate of ACh degradation would be of importance in synchronous
changes in ACh concentration in sinus node neuroeffector junctions with
high-frequency variations in vagus nerve activity (8). Similarly, the
slowing of ACh degradation by ChE inhibition would provide a mechanism for explaining our experimental observation that neostigmine decreased the corner frequency of the transfer function from vagal stimulation frequency to HR response; in other words, neostigmine administration resulted in a loss of vagally mediated high-frequency fluctuations in
HR.
Because anesthesia affects neural regulation of the cardiovascular
system (33, 34), there remains the possibility that anesthesia affected
the results to some degree. However, because we cut the efferent
pathways of both sympathetic and vagal systems, the effect of
anesthetics on the central nervous system should have little effect on
the present results.
In summary, we found that neostigmine markedly changed the
transfer function from vagal stimulation frequency to HR response. The
experimental observation that neostigmine decreased the corner frequency of the transfer function supports the notion that the low-pass filter characteristics of the transfer function might result
from the filter characteristics of ACh kinetics. Because the transfer
function may thus represent the characteristics of the rate-limiting
step in the signal transduction pathway elicited by vagal stimulation,
our findings may predict that the process of ACh degradation is the
rate-limiting step in vagal control of HR. Whether or not such an
interpretation is indeed true, it is rather clear from our study that
ChE activity plays an important role in determining the dynamic
properties of transduction from vagus nerve activity to HR.
| |
ACKNOWLEDGEMENTS |
This study was supported by a Research Grant for Cardiovascular
Diseases (6A-4, 7A-1, 7C-2, 9C-1) from the Ministry of Health and
Welfare of Japan, by a grant from the Science and Technology Agency of
the Encourage System of Center of Excellence, and by a
grant from the Sankyo Foundation of Life Science.
| |
FOOTNOTES |
Address for reprint requests: K. Sunagawa, Dept. of Cardiovascular
Dynamics, The National Cardiovascular Center Research Institute,
5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Received 2 September 1997; accepted in final form 27 April 1998.
| |
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Abstract
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