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A book by
William H. Calvin
UNIVERSITY OF WASHINGTON
SEATTLE, WASHINGTON   98195-1800   USA
The Cerebral Symphony
Seashore Reflections on the
Structure of Consciousness

Copyright ©1989 by William H. Calvin.

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5

The Electrically Exciting Life
of the Inhibited Nervous Cell

Men ought to know that from nothing else but from the brain come joys, delights, laughter and sports, and sorrows, griefs, despondency and lamentations.
Hippocrates (460-377 B.C.)
How is it that I am a collection of a hundred billion nerve cells, yet I think and act as one?
the neurophysiologist Rodolfo Llinás, 1986

Several centuries ago, we were remarkably ignorant of how the brain worked, this despite the brain being identified as the seat of thought and feeling by each of the four great ancient civilizations: Mesopotamia, Egypt, India, and China. Or at least by some of their best thinkers (Egyptian embalmers still threw out the brain but attempted to preserve the heart and liver). The brain as "where all the action is" didn't become part of the everyday concepts of educated people until much more recently.
      With the Enlightenment and the Industrial Revolution came a gradual improvement in knowledge about the brain; by the end of the nineteenth century, many of the major neurological disorders had been identified, and the brain was seen to be made up of a great many cells organized in spectacular ways. Here, surely, were the parts from which one could construct an explanation for the major mental phenomena.
      Such fin de siècle figures as Sigmund Freud show us how frustrated the basic scientists were, trying to understand how brain components related to the higher mental functions and their disorders; Freud finally switched from studying stained nerve cells under a microscope to listening carefully to his neurotic patients for indications about how higher levels of functioning became disordered. Trained in the mechanistic physiology of Helmholtz, Freud would probably have been one of the first to suspect that his disorders of id, ego, and superego could be better described as the disordered activity of certain regions of the frontal lobe and subcortical structures; he would have loved to look at the rainbow-colored images thrown up on modern computer screens displaying the excessive metabolic activity of the inferior medial surfaces of the frontal lobes in obsessive-compulsive patients. Yet he too would have soon asked himself the question: "Ja, but why are those regions so active?" What causes them to "spin their wheels" and go nowhere?
      In earlier centuries, sages would probably have said that these poor individuals were simply "born under the wrong star" or that they (or their parents) had "sinned and were being punished by the gods for their transgression." But those who look more carefully, painstakingly developing the tools needed to get answers, have been finding that most brain disorders are either 1) incidental consequences of strokes and tumors; 2) disordered development of the brain in utero (essentially, gross miswiring by the standards of modern human brains) that manifests itself in later life as mental and neurological disorders; or 3) more subtle and labile disorders in the chemical systems used to communicate between nerve cells, also likely to be part of the variations thrown up by evolution.
      Indeed, part of the local history of Woods Hole is all tied up with this gradual improvement in our understanding of ourselves; you see reminders when walking around town.

Discovery consists of seeing what everybody has seen
and thinking what nobody has thought.

the Hungarian biochemist Albert Szent-Györgyi, 1962

OUT TO SEE THE SEA, or at least semiprotected Vineyard Sound. A few blocks east of Eel Pond and the Marine Biological Lab, one passes the Little Harbor, complete with coast-guard station. Looking down on it from the shore is the Woods Hole Library. Little Harbor opens out onto the choppy Woods Hole channel (locally called "the Hole") that connects Vineyard Sound to Buzzards Bay.
      Along this main road toward Falmouth is the headquarters of the Woods Hole Oceanographic Institution, where much basic research is also done (and applied research: One sometimes trips over television camera crews on Woods Hole sidewalks, if one of the WHOI ships is just back from exploring the deep-water wreck of the Titanic by remote-controlled "robots").
      Then one turns down Church Street. It is so-named because it has a church on it, just as School Street has a school on it (Water Street once had water along it, until they built a platform out over the water on stilts -- and then paved it!). Not far down Church Street beyond the wooden bridge, one comes to the church and surrounding graveyard.
      The Church of the Messiah is, like Woods Hole Library, a stone structure pieced together from all the local glacial debris, weathered down to a certain softness. This church is where the Woods Hole Cantata sings its annual concert every August (I've been listening to them practice up in the Meigs Room). Except for the distant drone of a lawn mower, the church is silent today, as is the graveyard alongside.
      I wander amongst the tombstones, looking for familiar names. There is a prominent new tombstone:

Albert I. Szent-Györgyi,
1893-1986,
Nobel Laureate
followed by an inscription in Hungarian. And many surnames familiar to a neurophysiologist are found here, as if the local families had contributed more than their share of brain scientists. Other names are scientists who moved here, often escaping from Hitler's mad designs.
      Otto Loewi is buried here, just downhill from the back of the church. The modest red tombstone says that he died in 1961 at the age of eighty-eight, the same year that I was taking my first physiology course. I never met him, but his discoveries were not only central to understanding the brain but important to me personally. I've since found out quite a lot about him, both from the people around Woods Hole and elsewhere (I ran into Loewi's one-time bottlewasher in California, now the novelist Ramón Sender Barayon).

BACK AT THE TURN OF THE CENTURY, it was known that nerves ran on electricity of some sort -- and so, presumably, did that enormous collection of nerve cells we call the brain. But the anatomists were still arguing about a particularly fundamental issue: Are the nerve cells really independent, as much so as the individuals in our society -- or do they constitute one big web of interconnected cells, where (at least functionally) it is hard to tell where one cell leaves off and another starts?
      You don't have to go to a coral reef to find examples of the latter arrangement: our hearts are like that. So it wasn't a trivial issue: The electrical current generated by one heart cell spreads to neighboring cells easily because the cell membranes stick together and open up holes that connect the inside of one cell to the inside of its neighbors.
      Various prominent histologists and neuroanatomists at the beginning of the twentieth century said brains were reticulated webs something like that. However, the great Spanish neuroanatomist Santiago Ramón y Cajal (1852-1934) essentially said that nerve cells were more like the individuals of our society lightly touching one another via outgrowths ("Holding hands with one another" was the way he put it) -- but not kissing continuously. It's something like the holistic versus reductionistic arguments, the whole brain acting as an indivisible whole versus acting as a collection of independent agents, each different.
      And Loewi (pronounced rather like "Levi") is the fellow who settled the argument in Cajal's favor (at least to most physiologists' satisfaction; the anatomists weren't really convinced until 1953, when Sandy Palay's electron micrographs demonstrated the narrow synaptic cleft separating nerve cells). Loewi was the German physiologist and pharmacologist who discovered the key feature of how nerve cells interact with each other; he demonstrated that nerve ends release chemical "neurotransmitter" molecules that act as a messenger substance rather like a hormone. That's how most nerve cells affect the next nerve cell in a chain: They release a little puff of molecules that diffuse a short distance and stimulate the next cell into electrical action, rather as the perfume advertisements claim that the barest whiff of their scent will stimulate social electricity. We now know that some nerve cells are tightly linked in the heartlike manner; indeed, many cells are, at one stage or another of prenatal development (that's one of the things that my wife studies at Woods Hole, the electrical coupling of the sixteen-cell stage of squid), but most nerve cells lose it later and substitute the perfume trick.
      Loewi originally wanted to be a historian of art, but he dutifully went to medical school, bowing to family pressures (similarly, Ramón y Cajal's plans to become a painter were thwarted by his father). Discouraged with the poor therapies of his day, Loewi later went into pharmacology research. He was one of the first people to propose that cells talked to one another with little whiffs of scent (well, more formally known as the chemical theory of synaptic transmission). Back in 1903, that was an interesting idea, but several decades later it was in general disrepute, no one having been able to design an experiment that would really force one to believe or disbelieve in it. Most interesting ideas aren't ever disproved: They just fade away.
      One night in 1921, just before Easter Sunday in Graz, Austria, Loewi fell asleep while reading a light novel. Some hours later, he awoke suddenly with this marvelous experimental design for proving that chemical transmission existed between the vagus nerve and the heart. Not trusting his memory, he wrote it down on a thin scrap of paper. And went happily back to sleep.
      He awoke early the next morning and remembered that something important had happened, but he couldn't remember what. Then -- happy relief -- he discovered the note that he had written himself. But the brief message was incomprehensible. Loewi went around distracted all day, trying to remember what the idea was, mystified as to the meaning of the cryptic note that he had written to himself. Finally, he went to bed, in hopes that the dream would recur.
      And indeed the dream did recur, and he awoke again at three in the morning. This time, he didn't write himself a note. Instead, he climbed out of bed, got dressed, and immediately went to his lab. And performed the critical experiment that forces everyone to accept the fact of chemical intermediaries at the gaps between cells, transforming an electrical signal into this "whiff of perfume" and then back into electrical signals again.
      There are two major classes of chemical messengers, excitatory ones and inhibitory ones. Loewi did his work on the inhibitory connection to the heart, studying how the vagus nerve coming down from the brain manages to get the heart to beat slower. It had been known that one could mimic the brain's activation of this nerve by simply shocking the nerve repeatedly: These "jump starts" inelegantly produce nerve impulses identical to those started in the brain by more conventional means. The electrical impulses travel down the nerve rather like a burning fuse (or a string of firecrackers, in the case of the faster-conducting nerve fibers); when they arrive in the heart, they somehow slow down the beat. And it wasn't some roundabout effect: Loewi could take out the heart of a brain-dead frog, complete with attached vagus nerve, mount it in a lab dish, let it pump an oxygen-saturated blood substitute (just a fancy concoction of salt water called "Ringer's solution") to keep it supplied with oxygen, and show that the heart temporarily slowed its rhythmic beat whenever a few stimuli were given to the nerve.
      Otto Loewi's middle-of-the-night experiment was simplicity itself: He took a second heart removed from a second frog, but left behind its vagus nerve. He took the blood substitute coming out of the first heart and used it as the "venous blood returning," the input to the second heart, a kind of artificial transfusion. The second heart thus pumped the same "blood" that the first heart had just expelled a second earlier.
      Both hearts sat there beating away (their own internal pacemakers keep them going, unlike many muscles). Then Loewi stimulated the vagus nerve to the first heart. The first heart slowed down its beat. And just as Loewi had guessed, the second heart then slowed down too, just as soon as the blood substitute reached it from the first heart. The fluid was carrying along the inhibitory messenger substance that vagal-nerve impulses had caused to be released into the first heart. Evidently, so much was released that there was enough left over to slow the second heart as well.
      He not only proved that a chemical messenger (now known to be acetylcholine) was used to slow down the heart rate, but he later proved with analogous experiments that the cardioaccelerator nerve to the heart used a chemical (now called epinephrine or adrenaline) to speed up heart rate. It now seems particularly appropriate that his dream facilitated the discovery of acetylcholine's role as a neurotransmitter -- it turns out to be used by the neural system in the brain that facilitates dreaming!

DESIGNING EXPERIMENTS is just a particular art form related to the scenario-spinning that we use to plan shopping trips and careers. And so it is tempting to engage in a little dream analysis to see if we can understand how Loewi's subconscious stage-managed this elegant insight. Despite the "Eureka!" aspect, one can see that all the pieces of this simple but elegant experimental design had been present for years before 1921, in the possession of many physiologists around the world (especially the English school working hard on reflex organization); all that Loewi's subconscious finally did was to piece them together. Loewi had uttered the chemical messenger idea eighteen years earlier (he didn't publish it, but an English physiologist who visited Loewi's lab in Austria remembers him having mentioned it in 1903). The chemical intermediary possibility was common currency among researchers after about 1904. Later, in 1918 and 1919, Loewi had used the blood substitute method for studies on how ions (especially calcium) affected the heartbeat. When Loewi switched the solution from the normal salt concentration to the altered composition, the heart would speed up or slow down as soon as the new solution reached it. What Loewi's unconscious had linked together in 1921 was using this method to investigate the chemical transmission hypothesis; rather than the calcium of his blood substitute affecting heart rate, perhaps the stuff released by the vagus nerve would affect the second heart's rate? (Acetylcholine was originally called vagustoff by Loewi, literally "the stuff from the vagus").
      His elegant demonstration that the nerve's electrical message was mediated by the release of chemicals won him the Nobel Prize in Physiology or Medicine in 1936 (along with Henry Dale, who discovered acetylcholine in 1914). But the Nazi government extorted the prize money from Loewi as a condition for allowing him to leave (he was considered undesirable because of having chosen the wrong parents). He first fled to Brussels, and then to Oxford. In 1940, he became a research professor at New York University and started spending his summers in Woods Hole at the MBL. People who were around MBL in those days recall how Loewi liked to go for a swim at Stony Beach; they'd see him floating out there in Buzzards Bay, his pipe sticking up in profile against the skyline.
      Later it was shown that the slowing action of acetylcholine could be blocked by a drug called atropine. You set up the frog heart, stimulate the vagus repeatedly until the heartbeat stops. But before the next trial, after the heart has recovered, you add atropine -- whereupon you can stimulate the vagus nerve all you want, and the heart will take no notice of your stimuli. Atropine seems to have disconnected the vagus nerve from the heart! That's very impressive to demonstrate to students.

IT'S EVEN MORE IMPRESSIVE when it is one's own vagus nerve and own heart; it certainly gets your attention. The "flu" does some funny things to nerves on occasion. Just when I thought that I was getting over a mild case, I started having heart trouble: Blood pressure and heart rate were fluctuating all over the place. And so I went to see my physician, who promptly sat me down in a wheelchair and had me rolled across the street to the hospital's cardiac ICU. I protested all the way, not feeling shaky. When they finally got me installed in the hospital room and hooked up all the monitors, I was resigned to a day of hospital routine. But I was very impatient, not having brought anything to read. The nurses tried very hard to get me to lie back in bed. Finally, I did, if only because they insisted on hooking up an oxygen tube to my nose. And technicians kept coming around to take blood samples, or to hook up a venous catheter "just in case" they needed to rapidly inject a drug.
      It was in the midst of one of these blood-letting sessions that I suddenly felt funny, tingling sensations coming from both my hands and feet. I knew that arterial punctures could be unpleasant, something like a bee sting, but this was clearly systemic in a big way. Whatever it was, it didn't feel so good -- and so I told the technician to call the nurses. But they came on the run anyway, because the cardiac monitor had set off an alarm. Almost immediately I had six people surrounding me, half looking at the EKG display over my head and the others doing things like propping up my legs, or increasing the oxygen flow, or checking my blood pressure repeatedly.
      I was all but unconscious: The world was slowly fading out amid an incredible barrage of tingling in all extremities. You know how, when you're traveling abroad, trying to listen to the BBC or the Voice of America on a shortwave radio, and you hear the static level rising and the announcer's voice fading out simultaneously? And you never get to hear the rest of the newscast? That, insofar as I experienced it, is how consciousness ends.
      Talk about Primal Questions: How does one stay tuned in?

THAT I REMAINED CONSCIOUS (or should I have said "retained awareness"?) through it all was only because they were giving me pure oxygen to breathe -- otherwise a blood pressure of 60/45 will cause one to faint and miss all the excitement, that crescendo of tingles. My heart hadn't stopped completely, but it wasn't for lack of trying by the vagus nerve: The regular pacemaker at my sino-atrial node was completely silenced by massive amounts of vagal inhibition. This caused a backup pacemaker in the atrial-ventricular node to start beating. But it was generating heartbeats at too slow a rate to maintain a decent blood pressure.
      I didn't know all of this at the time. All I knew was that I suddenly began to feel much better, and that the world started to come in loud and clear again. The tingles stopped. I wasn't ready to hop out of bed, but it was quite clear that I'd been snatched back to a safe harbor.
      What the cardiology resident had done when she saw the EKG (it was missing the little initial bump called the P-wave that indicates the S-A node is initiating the heartbeat) was to inject some atropine into a vein. The atropine stopped the acetylcholine from inhibiting the heart pacemaker (the pacemaker cells have little "locks" in their membrane to which acetylcholine acts as the "key" -- except when the "keyhole" is plugged by atropine). And so the S-A node started beating again, and at a normal rate that could maintain a normal blood pressure. That's when I began feeling better.
      And why had my vagus nerve been acting as if it were being repeatedly stimulated in the manner Otto Loewi treated those frog vagus nerves? Was my brain telling my heart to shut up, emphatically?
      No. It was a false message, inserted into the nerve. The nerve had run amok in very much the way that other nerves do when they cause muscle cramps. What happens is that the nerve endings begin producing nerve impulses on their own, "jump-starting" themselves rather than being faithful followers of what the brain tells them to do.
      In the case of a leg muscle, this causes sustained contraction of the muscle, so much that it becomes painful. There is no voluntary way to relax the muscle, as the extra nerve impulses are coming from the nerve endings embedded in the muscle, not from the brain or spinal cord in the manner that impulses usually do. In the case of the vagus-nerve "cramp," the barrage causes complete inhibition of the heart pacemaker. Instead of feeling pain, one faints (except when oxygen is provided). Such an intense barrage eventually depletes the stockpile of acetylcholine, so that the heart's pacemaker may eventually resume even if the impulse barrage continues.
      So the problem wasn't with my heart, but with the vagus nerve endings in the heart. And like muscle cramps, the problem usually goes away in a few days, probably because some disrupted insulation on the nerve is repaired. They kept me around the cardiac ward for a few more days to run tests to be sure that there wasn't something else wrong. But nothing else happened after that first hour. Eventually, they kicked me out.
      That's a story that is repeated every day in one modern hospital or another, but most patients can't reconstruct what happened. They're just very happy that the physician knew what to do, and why. That knowledge came from basic research by physiologists and pharmacologists experimenting on various animal species (most heart research requires dogs). Most of the research achievements aren't as easy to communicate as Otto Loewi's story, but they all have similar elements: an idea about how it might work, a clever experimental design that provides a believable answer, and then a new wave of developments that make use of the now-known mechanism to solve additional problems like the atropine blockage.
      My great relief that day when I was brought back from Tingleland was due to that research, most especially Otto Loewi's. And so Professor Loewi is remembered by far more people than happen to see his gravestone at the Church of the Messiah in Woods Hole -- hundreds of thousands of medical students have learned about Otto Loewi and the discovery of neurotransmitters. Some have even heard about the workings of his subconscious.

IN A NEWER SECTION OF THE CHURCHYARD, there is a small, flat stone, overgrown by the grass, for Stephen W. Kuffler, who died in 1980. He was a teacher of mine, when I took the neuroscience course at Harvard Medical School back in 1962, and I've probably read most of the scientific papers that he wrote before and since.
      Steve was a follower of Otto Loewi in a number of ways: He also escaped the Nazis, worked on acetylcholine and inhibition. Born in Tab, Hungary, he was reared on a farm and had no formal schooling until he was ten years old. After graduating in pathology from the University of Vienna in 1937, he went to Australia during the war and there became involved in basic research on nerves, showing that acetylcholine sensitivity in muscles occurred only in a specialized region close to the nerve endings. And he did the classical analysis of how an inhibitory synapse actually works when the downstream cell is a nerve cell rather than a heart pacemaker.
      In 1971 he showed how the vagus nerve actually slows down the heart by activating an intermediate nerve cell. Hidden in the heart wall, right in the thin septum between the two upper chambers of the three-chambered amphibian heart, are some tiny nerve cells. They're what the vagal nerve ends upon, not heart muscle directly. These little "parasympathetic ganglion" cells are what actually release the acetylcholine that slows the heart pacemaker -- when the vagus nerve tells them to do so by releasing acetylcholine. Kuffler searched and searched (I remember him saying that he spent six solid months in the Harvard Medical School library), trying to find an animal whose neurons were embedded in a transparently thin muscle, so that he could put that sheet of muscle under a microscope and see the nerve cells at the same time that he maneuvered electrical-recording leads in their vicinity. The frog had a particularly thin septum, and a dozen parasympathetic nerve cells clearly visible. This 1971 experiment that he did with Jack McMahon marked the beginnings of a new standard in "seeing what you're doing."
      They could cut the vagus nerve a few days earlier and show how these cells "got lonely" when deprived of their contact with the outside world; the denervated cells turned up their sensitivity so high that they would respond even without vagal input, a cellular version of the hallucinations one experiences if deprived of all sensory input. That kind of sensitivity adjustment is thought to be what happens in patients who experience phantom-limb pain, who report that their big toe hurts even though the leg was amputated in an industrial accident. We haven't yet discovered how to relieve such patients of their disabling pain, in the manner of atropine for the pacemaker standstill, but when we do, it will likely owe something to Steve Kuffler and his co-workers, who managed to see the sensitivity-adjusting process at work in those little nerve cells inside the heart wall.
      Many of the major neurological and mental disorders (those that aren't due to strokes and gross developmental disorders) seem to involve neurotransmitters like those Otto Loewi found: There may be too much, or too little, or an effect lasting too long. And the number of keyholes in the next nerve cell can be too great, as seen in Steve Kuffler's denervated nerve cells inside the heart wall. Whatever, it disrupts the music of movement. Finally, a century after Freud abandoned his microscope, we have the concepts like synaptic regulation, and we have some tools such as the brain-imaging devices that can measure neurotransmitter and receptor distribution inside a living brain, that may allow us to understand schizophrenia, depression, obsession, and the variety of more common mental ailments that occasionally disable many of us.

EFFECT AND COUNTEREFFECT, as seen in all these examples of push-and-pull together, may sound a bit like Newton's Third Law ("For every action there is an equal and opposite reaction"), what pushes rockets forward at the same time as exhaust gases rush backward. But principles in biology are mostly guides: If you see a process doing one thing, like exciting a nerve cell, look around and you'll probably find an opposing process, such as an inhibitory synapse. In the heart, the cardioaccelerator nerve's actions are opposed by the vagus's slowing actions.
      Neurosurgeons made good use of this principle in developing surgical relief for Parkinson's disease: A virus destroys cells in the substantia nigra, part of a system that tends to inhibit a postural control system, and so patients get "uptight," excessively stiff. So the surgeons tried destroying a perfectly good piece of the brain (the ventrolateral thalamus normally has the opposite effect on the system), and so brought the system's excitation and inhibition back into balance.
      But as a principle -- well, the first thing that you find are exceptions to the rule. Look at our smooth muscle, or the leg muscles of insects, and you'll find "peripheral inhibition" like that of the vagus nerve upon the heart. But there is none in mammalian skeletal muscle. Our skeletal muscles receive only excitation, never inhibition. In our case, the push-and-pull balancing act is all done back at the motorneurons in the spinal cord that run the muscle; the muscle then just does what the motorneuron tells it to do (except in "cramps"!). As a result, the touch receptors in the skin overlying the muscle cannot influence the muscle except by the long trip into the spinal cord, where their recommendations are judged in the light of thousands of other influences on the motorneuron, and then a message is sent back out to the muscle, telling it to contract. It takes time for that long round trip, and sometimes that's important.
      Still, all brain cells receive both excitatory and inhibitory synapses -- about half and half, in most of the cells where they've been counted. And so each brain cell is a little computer, adding up an account balance of all the deposits and withdrawals, seeing how much interest to pay out to the cells it talks to. The brain is a society of billions of those little computers; occasionally the cells act together as a mob, but usually they all go their own way -- and so do many different jobs at the same time. We need to learn the sociology of this society -- we hardly even know the grossest phenomena, such as the mob actions of epileptic seizures, when we badly need to know its system of checks and balances. Perhaps when we learn the nuts and bolts -- the job that Loewi and Kuffler started -- we will be able to understand how new abilities emerge from the compounding of the parts.

BIOLOGY SHAPES UP ORDER since it provides a memory of the past via which genes survive and which drop out; each one of us, in each of our cells, is guided by the history of ancestor organisms extending back 3 billion years. Whenever I throw a baseball, I am aided by the successes and failures of my ice age ancestors who threw to hunt. Those memories are encoded in the gene pool; cultural evolution provides even more detailed memories. Whenever I think about a problem, I am aided by the successes and failures of untold past generations in dealing with various problems -- Archimedes' still-successful analysis of floatation and Aristotle's attractive but nonsensical physics shape the way I think about cars and boats. Loewi and Kuffler speak to me still through their writings and my conversations with their students.
      As I left the churchyard, I thought about how much of our modern world is due to a relatively few people pursuing abstract ideas, out of the billions who have lived on earth. Ideas that work. Until recently, most such long-term-payoff research was done by stealing time from teaching students or treating patients. But today, mostly in the last four decades, we see whole institutes devoted to basic research. They are the leading "industry" of Woods Hole. In the future, there will be people who owe major debts to the researchers who think and labor here, just as I am indebted to Otto Loewi.

I've been freed from the self
that pretends to be someone,
And in becoming no-one,
I begin to live.
It is worthwhile dying,
to find out what life is.
T. S. Eliot
The Cerebral Symphony (Bantam 1989) is my book on animal and human consciousness, using the setting of the Marine Biological Labs and Cape Cod. AVAILABILITY is limited.
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