DRUGS THERAPY OF STRESS
ON UPPER RESPIRATORY TRACT INFECTIONS EASINESS IN DOWNS: A SURVEY ON ONE-YEAR
AND TWO-YEARS RESULTS
Renato COCCHI MD, neurologist and medical
psychologist
Abstract
T'hís is a retrospective study of a series
of 185 home-reared Down Ss. All they had therapies for one
year, 145 of them for two years, because presenting various
degrees of easiness to Upper Respiratiory Tract infections (URTI). 185
Ss sample data: 96 M and 79 F,, M/F ratio = 121.52,, chromosomal
diagnosis. standard trisomy 21 = 90.81%; mosaicisms = 3.24%;
transiocations = 5.41%; only clinical diagnosis.- 0.54%; Average age at first
consultation: 56.83 +/- 49.35 months, average therapy length: 60..99 +l-
42.18 months. 145 Ss sample data: 79 M and 66 F, MIF ratio = 119. 70,-
chromosomal diagnosis. standard trisomy 21 = 90.34%; mosaicisms = 3.45%;
transiocations = 5.52%; only clinical diagnosis: 0.68%. Average
age at first consultation. 55.50 +/- 49.70 months,- average therapy
length: 73.42 +l- 3.9.41 months.
The reduction of URTI
easiness after l-year or 2-years drug therapy was highly significant (0009 for
both samples). The disappearance of ít took place in 20.53% after one-year
therapy and 41.38% after two-years therapy. As seen in children up to nine
years old 155 Ss) and up to eight years (116 Ss) at 1st consultation,
the age growing favoring effect was considered as negligible.
The papa reports the
list of drugs prescribed at 1st consultation - mainly , pyridoxine and a low
dose benzodiazepine
-, with their daily doses. The same for the percent of any drug used and the
rationale for theír use.
Key words: Downs
syndrome; Upper Respiratiory Tract Infections; Easiness; One-year drug therapy,
Two-years drug therapy.
Mental retardation
Drug modulation of stress reaction
In my previous research (Cocchi, 1997) 1
investigated the time-course of easiness to Upper Respiratiory Tract lnfections
(URTI) in 510 non-drug-treated Downs, as reported at first consultation. In
another research (Cocchi, 1998) l evaluated global therapy results on URTI
easiness in 328 Downs with only consideration of the age at the last checkup.
Then l compared it with matched age non-treated subjects. In this way l could
divide the specific effect of the drug therapy on this easiness from its usual
reduction due to age effect.
Since this was showing as an early
and quite firm effect, l thought to plan another research where scoring it at a
fixed distance from first consultation. Although there l reached very positive
results, i was sure that fixed times of scoring after one-year and two-years
drug therapy would have brought more information. This new research on this topic
refers to the effect of drugs after these intervals from the treatment
beginning.
Materials and methods
The current surveyèy deals with the clinical
records related to all subjects who took the prescribed drug therapy and had
one-year or two-years-checkups after the first visit. This makes a casual
consecutive series of Downs that has its selective criterion on those Down Ss
having come back for checkups at least for this minimum time. As home-reared
and home-living Downs they came from all parts of ltaly to outpatients'
consultations, between January 1979 and April 1997.
During their 1st consultation all these Ss
had their easiness to URTI evaluated and recorded by severity, along with other
signs and symptoms. The scoring of that easiness had its reference to the past
12 months (or, in children aged less than one year, to past therapy months) by
recording according to a severity scale as follows:
(0) = as in a healthy child;
- = nasal catarrh usually present;
- = 1 + susceptibility to cough and cold with few feverish episodes;
(3) = 1 + 2 + easiness to tonsillitis,
pharyngitis, bronchitis vith moderate fever and limited need of antibiotics (up to four regimens per year);
(4) = 1 + 2 + 3 + high temperatures,
occasional otitis- ánd bronchial pneumonia, and frequent use of antibiotics
(more than four regimens per year).
l used the same scoring way during following
checkups.
The records about autistic or PDDs Ss were
discarded because we saw that this second heavier pathology can modify the URTI
easiness (Cocchi and Bonaduce, 1988).
From the remaining records I collected: sex,
chromosomal diagnosis; age at 1st consultation; scoring of URTI easiness at 1st
consultation; the same at on-year or two-years checkups; follow-up; drugs
prescribed at the first checkup and their daily doses.
I processed data by means and URTI easiness graduation and l applied
Wilcoxon's Signed Ranks Test or Chi Square Test when suitable.
Results
Only 185 cards for the one-year survey, and
only 145 cards for the two-years survey out of 510,fitted those criteria. They
refer to home reared Downs coming from all Italy.
Tables 1-2 and 12 summarize epidemiological
data of the samples, table 3 shows drugs prescribed at first consultation. Then
Tables 4-11 and 13-15 present the URTI easiness scoring according to one-year
or two-years survey.
In graphics 1-4 1 showed the variation of
URTI easiness according to each grade of seventy, both for the 185 Ss sample
and the 145 Ss sample. The same i did for the samples of 155 and 116 Ss, where
the favoring age growing variable got out.
Table 1: epidemiological and clinical data
of the sample related
to the one-year survey (185 Ss)
|
No. of Ss |
185 |
100.00% |
|
M |
96 |
57.30% |
|
F |
79 |
42.70% |
|
M/F |
121.52 |
|
|
Chromosomal diagnosis |
|
|
|
Standard trisomy 21 |
168 |
90.81% |
|
Mosaicisms |
6 |
3.24% |
|
transiocations |
10 |
5.41% |
|
Unknown, only clinical diagnosis |
1 |
0.54% |
|
Age at 1st consultation, range in months |
4 - 280 |
|
|
Average +/- SD |
56.83 +/- |
|
|
Follow-up, range in months |
12 - 169 |
|
|
Average +/- SD |
60.99 +/- |
|
As we can see in Table 1 the M/F ratio does
not fully overlap what we know for live born Italian infants. The distribution of
the chromosomal diagnoses stays within the variance limits for Italian and
International samples.
Although the slight reduction of the male
prevalence, we can assume the sample here surveyed as a representative sample
at least of the ltallan population of Downs.
Table 2: Epidemiotogical and cIinical data
óf the sample
related to the two-years survey (145 Ss)
|
No. of Ss |
145 |
100.00% |
|
M |
79 |
54.48% |
|
F |
66 |
45.52% |
|
M/F |
119.70 |
|
|
Chromosomal diagnosis |
|
|
|
Standard trisomy 21 |
131 |
90.34% |
|
Mosaicisms |
5 |
3.45% |
|
transiocations |
8 |
5.52% |
|
Unknown, only clinical diagnosis |
1 |
0.68% |
|
Age at 1st consultation, range in months |
4 - 280 |
|
|
Average +/- SD |
55.50 +/- |
|
|
Follow-up, range in months |
24 - 169 |
|
|
Average +/- SD |
73.42 +/- |
|
As we can see in Table 2 the M/F ratio does
not fully overlap what we know for live from IItalian infants. The distribution
of the chromosomal diagnoses stays within the variance for talon and lnternational
samples. Although the slight reduction of the male prevalence, we can assume
this sample as representative for at least the ltallan population of Downs.
Table 3: Drugs prescribed at first
consultation and their daily doses.
|
Drug in use |
mg/die |
No. of Ss |
% |
|
Pyridoxine (*) |
75-150 |
185 |
100.00 |
|
L-glutamine |
125-250 |
159 |
85.94 |
|
L-glutamine + pemoline (**) |
45+5 - 90+10 |
26 |
14.06 |
|
Diazepam |
1-2.5 |
163 |
88.11 |
|
Bromazepam |
0.5-1.5 |
16 |
8.11 |
|
Oxazepam |
7.5-15 |
7 |
3.77 |
|
Folates (*) |
7.5 |
31 |
16.76 |
|
Total |
|
586 |
|
(*)In many cases the drug
was prescribed every second day by alternating pyridoxine and folates, so the
daily dose reports !t as lf it was prescribed every day.
(**) No more marketed in
ltaiy
The average prescription summed up 3.16
drugs per person. Glutamine, alone or in combination with pemoline, pyridoxine
and a low dose benzodiazepine was the basic regimen.
Tab. 4: Comparison of the results in the
whole sample (185 Ss)
|
URTI easiness' graduation |
Initial scores |
Final scores |
||
|
|
No. of Ss |
% |
No. of Ss |
% |
|
Not present (O) |
0 |
0.00 |
117 |
63.24 |
|
Present, mild (1) |
31 |
16.76 |
29 |
15.67 |
|
moderate (2) |
39 |
21.08 |
18 |
9.73 |
|
severe (3) |
79 |
42.70 |
16 |
8.65 |
|
Profound (4) |
36 |
19.46 |
5 |
2.70 |
|
Totals |
185 |
100.00 |
185 |
100.00 |
|
Average severity +/- SD |
2.65 +/- 0.98 |
0.72 +/- 1.11 |
||
Wilcoxon's Signed Ranks Test: z = 10.786 and
p < .0009
As a global survey, at final scoring only
about 37% of the sample went along to present URTI easiness. On the other hand,
increased severity (grades 3-4) went down from about 62% to less than 12%.
Tab. 5: Comparison between initial scores and scores after one-year drug therapy in the whole sample (185 Ss)
|
URTI easiness' graduation |
Initial scores |
After 1-year therapy |
||
|
|
No. of Ss |
% |
No. of Ss |
% |
|
Not present (O) |
0 |
0.00 |
38 |
20.53 |
|
Present, mild (1) |
31 |
16.76 |
35 |
18.92 |
|
Moderate (2) |
39 |
21.08 |
51 |
27.57 |
|
Severe (3) |
79 |
42.70 |
47 |
25.40 |
|
Profound (4) |
36 |
19.46 |
14 |
7.58 |
|
Totals |
185 |
100.00 |
185 |
100.00 |
|
Average severity +/- SD |
2.65 +/- 0.98 |
1.80 +/- 1.24 |
||
Wilcoxon's Signed Ranks Test: z = 8.919 and p
< .0009
After one-year of drug therapy more than 20%
of the subjects lost their URTI easiness and severe forms (grades 3-4)
decreased from about 62% to about 33%.
Tab. 6: Comparison between one-year therapy scores and final scores in the whole sample (185 Ss)
|
URTI easiness' graduation |
After 1-year therapy |
Final scores |
||
|
|
No. of Ss |
% |
No. of Ss |
% |
|
Not present (O) |
38 |
20.53 |
117 |
63.24 |
|
Present, mild (1) |
35 |
18.92 |
29 |
15.67 |
|
Moderate (2) |
51 |
27.57 |
18 |
9.73 |
|
Severe (3) |
47 |
25.40 |
16 |
8.65 |
|
Profound (4) |
14 |
7.58 |
5 |
2.70 |
|
Totals |
185 |
100.00 |
185 |
100.00 |
|
Average severity +/- SD |
1.80 +/- 1.24 |
0.72 +/- 1.11 |
||
Wilcoxon's Signed Ranks Test: z = 9.163 and
p < .0009
As we can see in Table 6, the good result
after one-year of drug therapy is only a step towards a better one that needs a
longer treatment. Of course, as l have found in my previous paper (Cocchi,
1998), there is also a favorable effect due to becoming older.
Tab. 7: Global comparison between initial and final scores
in the two-years therapy sample (145 Ss)
|
URTI easiness' graduation |
Initial scores |
Final scores |
||
|
|
No. of Ss |
% |
No. of Ss |
% |
|
Not present (O) |
0 |
0.00 |
93 |
64.14 |
|
Present, mild (1) |
24 |
16.55 |
19 |
13.10 |
|
Moderate (2) |
28 |
19.31 |
18 |
12.41 |
|
Severe (3) |
62 |
42.76 |
11 |
7.59 |
|
Profound (4) |
31 |
21.38 |
4 |
2.76 |
|
Totals |
145 |
100.00 |
145 |
100.00 |
|
Average severity +/- SD |
2.69 +/- 0.99 |
0.72 +/- 1.11 |
||
Wilcoxon's Signed Ranks Test: z = 9.264 and p
< .0009
As a survey on the two-years therapy sample,
at final scoring only about 36% of the same sample went along to present URTI
easiness, but increased seventy (grades 3-4) went down from about 64% to less
than 1 1 %.
Tab. 8: Comparison of the results after one-year drug therapy (145 Ss)
|
URTI easiness' graduation |
Initial scores |
After 1-year therapy |
||
|
|
No. of Ss |
% |
No. of Ss |
% |
|
Not present (O) |
0 |
0.00 |
27 |
64.14 |
|
Present, mild (1) |
24 |
16.55 |
20 |
13.10 |
|
Moderate (2) |
28 |
19.31 |
43 |
12.41 |
|
Severe (3) |
62 |
42.76 |
42 |
7.59 |
|
Profound (4) |
31 |
21.38 |
13 |
2.76 |
|
Totals |
145 |
100.00 |
145 |
100.00 |
|
Average severity +/- SD |
2.69 +/- 0.99 |
1.96 +/- 1.24 |
||
Wilcoxon's Signed Ranks Test: z = 9.264 and p
< .0009
After one-year of drug therapy more than 18%
of the subjects lost their URTI easiness and severe forms (grades 3-4)
decreased from about 64% to about 38%.
Tab. 9: Results after two-years drug therapy
|
URTI easiness' graduation |
Initial scores |
Afrer 2-years therapy |
||
|
|
No. of Ss |
% |
No. of Ss |
% |
|
Not present (O) |
0 |
0.00 |
60 |
41.38 |
|
Present, mild (1) |
24 |
16.55 |
43 |
29.65 |
|
Moderate (2) |
28 |
19.31 |
23 |
18.86 |
|
Severe (3) |
62 |
42.76 |
14 |
9.65 |
|
Profound (4) |
31 |
21.38 |
5 |
3.45 |
|
Totals |
145 |
100.00 |
145 |
100.00 |
|
Average severity +/- SD |
2.69 +/- 0.99 |
1.14 +/- 1.13 |
||
Wilcoxon's Signed Ranks Test: z = 9.290 and p
< .0009
Tab. 10: Comparison between two-years and final
scores of the reduced sample (145 Ss)
|
URTI easiness' graduation |
After 2-years therapy |
Final scores |
||
|
|
No. of Ss |
% |
No. of Ss |
% |
|
Not present (O) |
60 |
41.38 |
93 |
64.14 |
|
Present, mild (1) |
43 |
29.65 |
19 |
13.10 |
|
Moderate (2) |
23 |
18.86 |
18 |
12.41 |
|
Severe (3) |
14 |
9.65 |
11 |
7.59 |
|
Profound (4) |
5 |
3.43 |
4 |
2.76 |
|
Totals |
145 |
100.00 |
145 |
100.00 |
|
Average severity +/- SD |
1.04 +/- 1.13 |
0.72 +/- 1.11 |
||
Wilcoxon's Signed Ranks Test: z = 5.488 and p
< .0009
As we can see in Table 9-10 the improved
result after two-years of drug therapy is only a second step towards a better
result that needs a longer treatment. Of course, as l have found in my previous
paper (Cocchi, 1998), there is also a favorable effect on the decrease of URTI
easiness due to the becoming older.
Tab. 11: Comparison between l-year and 2-years therapy scores (145 Ss)
|
URTI easiness' graduation |
After 1-year therapy |
After 2-years therapy |
||
|
|
No. of Ss |
% |
No. of Ss |
% |
|
Not present (O) |
27 |
18.62 |
60 |
41.38 |
|
Present, mild (1) |
20 |
13.79 |
43 |
29.65 |
|
Moderate (2) |
43 |
29.66 |
23 |
18.86 |
|
Severe (3) |
42 |
28.97 |
14 |
9.65 |
|
Profound (4) |
13 |
8.96 |
5 |
3.45 |
|
Totals |
145 |
100.00 |
145 |
100.00 |
|
Average severity +/- SD |
1.96 +/- 1.24 |
1.14 +/- 1.13 |
||
Wilcoxon's Signed Ranks Test: z = 7.999 and p
< .0009
Graphics 1-2.
The graphic 1-2 show that l-years drug
treated Ss are healthier not treated than they were non-treated, but final
scores are decidedly better.
Graphics 3-4:
The graphics 3-4 show that 2-years
drug treated subjects are heaithier than they had only one-year treatment, but
their final scores are again better.
To avoid any age bias, according to
Cocchi, 1998, in the next Tables I checked the results in children with less
than 1 0 at one-year or two-years therapy scoring.
Table 12: epidemiological and clinical data of the samples of children aged up to 9 or 8 at 1st consultation, related to the one-year or two-years survey (155 or 116 Ss)
|
|
Up to 9 yrs Ss |
% |
Up to 8 yrs Ss |
|
|
No. of ss |
155 |
100.00 |
116 |
100.00 |
|
M |
84 |
53.19 |
60 |
51.73 |
|
F |
71 |
45.81 |
56 |
48.27 |
|
M/F |
118.39 |
|
107.14 |
|
|
Chromosomal diagnosis |
|
|
|
|
|
Standard trisomy 21 |
143 |
92.26 |
106 |
91.38 |
|
Mosaicisms |
4 |
2.58 |
4 |
3.45 |
|
transiocations |
8 |
5.16 |
6 |
5.17 |
|
Age at 1st consult, range |
4-108 months |
|
4-96 months |
|
|
Average +/- SD |
39.46 +/- 27.91 |
35.10 +/- 23.10 |
||
While the distiibution of the chromosomal diagnoses
falls within the normal range, the M/F ratio does not do it because of
increasing cut down of the male prevalence.
Tab. 13: Comparison after 1 -year in the children up to 9 at 1st consultation (155 Ss)
|
URTI easiness' graduation |
Initial score |
After 1-year therapy |
||
|
|
No. of Ss |
% |
No. of Ss |
% |
|
Not present (O) |
0 |
0.00 |
32 |
20.65 |
|
Present, mild (1) |
27 |
17.42 |
27 |
17.42 |
|
Moderate (2) |
28 |
18.06 |
45 |
29.03 |
|
Severe (3) |
67 |
43.23 |
40 |
25.80 |
|
Profound (4) |
33 |
21.29 |
11 |
7.10 |
|
Totals |
145 |
100.00 |
145 |
100.00 |
|
Average severity +/- SD |
2.69 +/- 0.99 |
1.82 +/- 1.29 |
||
Wilcoxon's Signed Ranks Test: z = 8.346 and p
< .0009
After one-year drug therapy the positive results
on URTI easiness are highly significant and they cannot be due to the favoring
effect of age.
Tab. 14: Comparison after 2-years in the children up to 8 at 1st consultation (116 Ss)
|
URTI easiness' graduation |
After 1-year therapy |
After 2-years therapy |
||
|
|
No. of Ss |
% |
No. of Ss |
% |
|
Not present (O) |
0 |
18.62 |
48 |
41.38 |
|
Present, mild (1) |
19 |
13.79 |
32 |
29.65 |
|
Moderate (2) |
19 |
29.66 |
20 |
18.86 |
|
Severe (3) |
51 |
28.97 |
11 |
9.65 |
|
Profound (4) |
27 |
8.96 |
5 |
3.45 |
|
Totals |
116 |
100.00 |
116 |
100.00 |
|
Average severity +/- SD |
2.74 +/- 0.99 |
1.07 +/- 1.16 |
||
Wilcoxon's Signed Ranks Test: z = 8.312 and p
< .0009
In children treated by two-years drug therapy
before they were more than 10 years old the positive results are highly
significant and in this survey too we can refuse the favoring effect of age
growing.
Tab 15: arisen of 'scores after one-year and two-years therapy between first two
samples and age growing effect reduced samples.
|
URTI easiness' graduation |
After 1-year therapy |
After 2-years therapy |
||
|
|
Sample 1 |
Sample 3 |
Sample 2 |
Sample 4 |
|
Not present (O) |
38 |
32 |
60 |
48 |
|
Present, mild (1) |
35 |
27 |
43 |
32 |
|
Moderate (2) |
51 |
45 |
23 |
20 |
|
Severe (3) |
47 |
40 |
14 |
11 |
|
Profound (4) |
14 |
11 |
5 |
5 |
|
Totals |
185 |
155 |
145 |
116 |
Chi Square after one-year therapy: 0. 1 99
with 4 df and p = .995
Chi Square after two-years therapy: 0.297
with 4 df and p = .990
As we can see there is 1% or less of the
probability that both pairs of samples own a significantly different member of
the couple. This Jet us to esteem the growing age favorable effect as negligibie.
Graphic 5-6
Discusston
This second research on drug therapies for
URTI easiness in Downs enlightens more iinformafton on the time course of the
results as a function of the treatment's length. The graduation of the scale
used for scoring URTI easiness is the same I used in previous research (Cocchi,
1987, Cocchi and Bonaduce, 1988; Cocchi, 1990, Cocchi, 1997; Cocchi 1998).
The examined samples could represent at
least the ltallan population of 21 trisomics, but the M/F ratio is debatable.
It does not fully overlap what already found in live births of ltallan Downs
(Camera and Mastroiacovo, 1984). The distiibution of chromosomal diagnoses too,
is what usually found either in laity and foreign countries (Camera and
Mastroiacovo, 1984, Hook, 1981).
The drugs prescribed at first consultation,
as reported in Tab. 3, are all GABAergic drugs, folates and pemoline excluded.
Since the pioneering clinical study in depressed children (1981) normal and
Down children, with easiness to upper respiratory tract infections, were
successfully treated by Gabaergic drugs (1998).
Research showed that even psychological
stress undermines host resistance to infections through neuro-endocrine
mediated changes in immune competence (Boyce et al., 1995). It is the same for
every kind of stress of external or internal origin or both. The adrenergic
blockade improves cellular immune responses in humans, otherwise depressed by
the so called mental stress as one type of internal stresses (Bachen et al.,
1995).
Because the immune-suppressive action of
stress via the GABA impairment (Horger and Roth, 1995) and subsequent cortisol
hyper-incretion or hyper-activity (Dhabhar et al., 1996; Haessig et al., 1996;
Dantzer, 1997; Friedman and lrwín, 1997), the rationale to counteract this
easiness by drugs can get its explanation as it follows.
This treatment uses Gabaergic drugs like
I-glutamine as the precursor of GABA via l-glutamic acid (Laake et al., 1995;
Shupliakov et al., 1997); pyridoxine as the cofactor of all decarboxyiases, GAD
inclusive(Baxter,1976); a benzodiazepine as the sensitizer of type A Gabaergic
receptors (Bruni et al., 1980; Viukari, 1983; Schoch et al., 1985).
This 3-drugs' prescription works in a
synergistic way and can restore the glutamic-GABA pathways impaired by the
stress itself. The use of a benzodiazepine aims to resensitize type A Gabaergic
receptors, the first metabolic point where stress applies itself.
Without doing ít we can induce only the
increasing of glutamate the cytotoxic effects of which are now weli known. This
evening use of a benzodiazepine is the best way to restore sleep ( Viukari,
1983) often impaired by excess adrenergic stimulation. But it works also by
avoiding side-effects like daily drowsiness and muscle relaxation.
On the other hand I-glutamine is directly
involved in the nucleogenesis of rapid proliferating cells (Gismondo et al.,
1998). It is the donor of the N atom 3 and the N atom 9 of the purinic ring,
the first step in the synthesis of nucleic acids (Stryer, 1988). And by this
way it contributes to a better production of leukocytes (Heberer et al., 1996;
Newsholm & Calder 1997; Yoo, et al., 1997). These cells are the basis of
non-specific immunity. I always need to remind that this result, again found in
Downs, is not peculiar of them. My first clinical] research on this topic dealt
with 61 depressed children among which I treated my first patient with Down's
syndrome (Cocchi 1981).
Now we can sum up the reasoning that
prompted me to assume that Down children are in a permanent stress condition
(Cocchi, 1993). If there is a frequent URTI easiness that can have relief by
artistry drugs, and this easiness can refer to a stress effect, then there is a
stress condítion. Which kind of stress? I am maintaining that they deal with a
permanent metabolic stress due to the 150% overworking of all the metabolisms
the genes of which are in the chromosome 21, because of a third chromosome 21
In this investigation too the age favoring
effect, which seems starting to works in many children only when they are 10-12
(Cocchi 1998), was found of poor influence. In that previous survey we found a
surely "per se" positive effect of long lasting drug therapies till
10 years of age. This was confirmed by the early disappearance of more severe
forms since 8-10 years, a fact noted only since 16 years in non-treated
Downs (Cocchi, 1997).
Conclusions
This second retrospective study on narrowing
down of URTI easiness in drugs treated Downs bears out the previous one
(Cocchi, 1987). The positive results after one-year and two-years of treatment
cannot depend on the favoring vadabie of age growing and are highly
significant. When compared with last checkups of the same subjects, these
results have a lesser favorable extent.
This was exactly the purpose and the point
where I started the use of drug therapies in Down children'. Nevertheless many
other positive outcomes went out, as reported elsewhere Cocchi, 1990; Cocchi,
1991; Cocchi, 1992; Cocchi and Favuto, 1993)
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