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The US government uses an experimental thermobaric missile to level Raccoon City.This explains its particularly grotesque appearance. The final boss battle is against the Nemesis parasite, which, perhaps stimulated by the chemical soup it was dumped into, has managed to grow to enormous stature, partially bursting out of the corpse of its host. the problem is, she only kills the Tyrant half of the creature. When Jill melts off Nemesis's head, arm and most of its tentacles in the Dead Factory disposal room, she really does kill it.Third, its coat is likely armored somewhat against small arms, especially 9mm and 12 gauge shells magnum caliber rounds are able to stagger it more effectively.Thusly, the parasite can contribute to its host durability by growing and mutating to compensate for the damage it takes. Secondly, Nemesis is a gestalt entity it's mainly a Tyrant, but also an engineered parasitic organism inside the Tyrant's body.As seen in the first two games, it takes dedicated anti-tank weaponry to kill a Tyrant even if Nemesis is caught in the gas explosions at the restaurant/newspaper or the backfiring of its own rocket launcher, that's just not comparable to a more powerful and focused explosive.
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Firstly, Jill and Carlos never manage to attack Nemesis with anything more than comparatively small-arms fire.